Inhibitors of short-chain dehydrogenase activity for treating coronary disorders

ABSTRACT

A method of treating preventing, minimizing, and/or reversing congestive heart failure, cardiomyopathy, and/or reduction of cardiac ejection fraction in a subject in need thereof includes administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.

RELATED APPLICATION

This application claims priority from U.S. Provisional Application No.62/483,177, filed Apr. 7, 2017, the subject matter of which isincorporated herein by reference in its entirety.

GOVERNMENT FUNDING

This invention was made with government support under Grant No.P50CA150964, and 5F32DK107156 awarded by The National Institutes ofHealth. The United States government has certain rights in theinvention.

BACKGROUND

Congestive heart failure, one of the leading causes of death inindustrialized nations, results from an increased workload on the heartand a progressive decrease in its pumping ability. Initially, theincreased workload that results from high blood pressure or loss ofcontractile tissue induces compensatory cardiomyocyte hypertrophy andthickening of the left ventricular wall, thereby enhancing contractilityand maintaining cardiac function. However, over time, the leftventricular chamber dilates, systolic pump function deteriorates,cardiomyocytes undergo apoptotic cell death, and myocardial functionprogressively deteriorates.

Factors that underlie congestive heart failure include high bloodpressure, ischemic heart disease, exposure to cardiotoxic compounds,such as anthracyclines, and genetic defects known to increase the riskof heart failure.

Short-chain dehydrogenases (SCDs) are a family of dehydrogenases thatshare only 15% to 30% sequence identity, with similarity predominantlyin the coenzyme binding domain and the substrate binding domain. Inaddition to their role in detoxification of ethanol, SCDs are involvedin synthesis and degradation of fatty acids, steroids, and someprostaglandins, and are therefore implicated in a variety of disorders,such as lipid storage disease, myopathy, SCD deficiency, and certaingenetic disorders.

The SCD, 15-hydroxy-prostaglandin dehydrogenase (15-PGDH),(hydroxyprostaglandin dehydrogenase 15-(nicotinamideadeninedinucleotide); 15-PGDH; Enzyme Commission number 1.1.1.141;encoded by the HPGD gene), represents the key enzyme in the inactivationof a number of active prostaglandins, leukotrienes andhydroxyeicosatetraenoic acids (HETEs) (e.g., by catalyzing oxidation ofPGE₂ to 15-keto-prostaglandin E2, 15k-PGE). The human enzyme is encodedby the HPGD gene and consists of a homodimer with subunits of a size of29 kDa. The enzyme belongs to the evolutionarily conserved superfamilyof short-chain dehydrogenase/reductase enzymes (SDRs), and according tothe recently approved nomenclature for human enzymes, it is namedSDR36C1. Thus far, two forms of 15-PGDH enzyme activity have beenidentified, NAD+-dependent type I 15-PGDH that is encoded by the HPGDgene, and the type II NADP-dependent 15-PGDH, also known as carbonylreductase 1 (CBR1, SDR21C1). However, the preference of CBR1 for NADPand the high Km values of CBR1 for most prostaglandin suggest that themajority of the in vivo activity can be attributed to type I 15-PGDHencoded by the HPGD gene, that hereafter, and throughout all followingtext, simply denoted as 15-PGDH.

SUMMARY

Embodiments described herein relate to compositions and methods fortreating preventing, minimizing, and/or reversing congestive heartfailure, cardiomyopathy, and/or reduction of cardiac ejection fraction.The methods can include administering to a subject having or at risk ofcongestive heart failure, cardiomyopathy, and/or reduction of cardiacejection fraction, a therapeutically effective or prophylactic amount ofan inhibitor of 15-PGDH activity. The therapeutically effective orprophylactic amount of the 15-PGDH inhibitor can be an amount effectiveto prevent, minimize, and/or reverse congestive heart failure,cardiomyopathy, and/or reduction of cardiac ejection fraction as well asto promote cardiomyocyte survival, viability, and/or regeneration.

In some embodiments, the congestive heart failure, cardiomyopathy,and/or reduction of cardiac ejection fraction can result from underlyingfactors, such as hypertension, ischemic heart disease, cardiotoxicity(e.g., cocaine, alcohol, an anti-ErbB2 antibody or anti-HER2 antibody,such as trastuzumab, pertuzumab, or lapatinib, or an anthracyclineantibiotic, such as doxorubicin or daunomycin), myocarditis, thyroiddisease, viral infection, gingivitis, drug abuse; alcohol abuse,periocarditis, atherosclerosis, vascular disease, hypertrophiccardiomyopathy, acute myocardial infarction or previous myocardialinfarction, left ventricular systolic dysfunction, coronary bypasssurgery, starvation, an eating disorder, or a genetic defect.

Other embodiments described herein relate to methods of preventing orreducing the risk of any type of acute or delayed cardiotoxic eventsthat are common to subjects or patients treated with chemotherapeuticagents. The method can include administering to a subject treated with achemotherapeutic agent a therapeutically effective amount of a 15-PGDHinhibitor. The cardiotoxic event that is prevented or reduced caninclude, for example, myocarditis, and cardiomyopathy, which isindicated by a reduction in left ventricular ejection fraction (LVEF),and signs and symptoms of congestive heart failure (e.g., tachycardia,dyspnea, pulmonary edema, dependent edema, cardiomegaly, hepatomegaly,oliguria, ascites, pleural effusion, and arrhythmias).

Chemotherapeutic agents that may cause cardiotoxic events may include,but are not limited to, alkylating agents, antimetabolites, anti-tumorantibiotics (e.g., anthracyclines), topoisomerase inhibitors, mitoticinhibitors hormone therapy, targeted therapeutics andimmunotherapeutics. In certain embodiments, anthracyclines may beresponsible for causing cardiomyopathy and other cardiotoxic events whenadministered as a cancer therapy, and may be optimally administeredalone or in combination with one or more additional chemotherapeuticagents according to the embodiments described herein.

A strong dose-dependent association between anthracyclines andcardiomyopathy limits the therapeutic potential of this effective classof therapeutic agents. Administration of a 15-PGDH inhibitor incombination with anthracycline can prevent or reduce the risk of anytype of acute or delayed cardiotoxic events associated withanthracycline exposure allowing the treatment to be tailored to maximizethe efficacy of these drugs.

Examples of anthracyclines that may be administered according to theembodiments described herein include, but are not limited to,doxorubicin, epirubicin, daunorubicin, idarubicin, valrubicin,pirarubicin, amrubicin, aclarubicin, zorubicin, either administered as asingle agent or in combination with other agents. Examples of additionalchemotherapeutic agents that can be administered to the subject before,during, or after anthracycline administration include an anti-ErB2 oranti-HER2 antibody, such as trastuzumab, pertuzumab, or lapatinib.

The methods described herein may be used to prevent cardiotoxicityduring the treatment of any type of cancer including, but not limitedto, bone cancer, bladder cancer, brain cancer, neuroblastoma, breastcancer, cancer of the urinary tract, carcinoma, cervical cancer,childhood cancers (e.g., astrocytoma, brain stem glioma, NCS atypicalteratoid/rhabdoid tumor, CNS embryonal tumor, CNS Germ Cell tumors,craniopharyngioma, ependymoma, kidney tumors, acute lymphoblasticleukemia, acute myeloid leukemia, and other types of leukemia; Hodgkinlymphoma, non-Hodgkin lymphoma, Ewing sarcoma, osteosarcoma andmalignant fibrous histiocytoma of the bone, rhabdomyosarcoma, softtissue sarcoma, and Wilms' tumor), colon cancer, esophageal cancer,gastric cancer, head and neck cancer, hepatocellular cancer, livercancer, lung cancer, lymphoma and leukemia, melanoma, ovarian cancer,pancreatic cancer, pituitary cancer, prostate cancer, rectal cancer,renal cancer, sarcoma, stomach cancer, testicular cancer, thyroidcancer, and uterine cancer.

In some embodiments, a therapeutically effective amount of the 15-PGDHinhibitor administered to a subject in need thereof can be an amounteffective to increase or improve left ventrical ejection fraction, leftventricular end systolic volume, wall motion score index, and/or sixminute walk distance at least about 30 meters by at least about 2%, atleast about 3%, at least about 4%, at least about 5%, at least about 6%,at least about 7%, at least about 8%, at least about 9%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, or at leastabout 50%.

In other embodiments, a therapeutically effective amount of the 15-PGDHinhibitor administered to a subject in need thereof can be amounteffective to mitigate decreases in left ventrical ejection fraction,left ventricular end systolic volume, wall motion score index, and/orsix minute walk distance at least about 30 meters caused by cardiotoxiccompounds by at least about 2%, at least about 3%, at least about 4%, atleast about 5%, at least about 6%, at least about 7%, at least about 8%,at least about 9%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, or at least about 50%.

In other embodiments, the 15-PGDH inhibitor can be administered before,during, or after exposure to a cardiotoxic compound. In yet otherembodiments, the 15-PGDH inhibitor can be administered during two, orall three, of these periods.

In still other embodiments, the 15-PGDH inhibitor can be administeredeither prior to or after the diagnosis of congestive heart failure inthe mammal.

In some embodiments, the 15-PGDH inhibitor can be administered to asubject at an amount effective to increase prostaglandin levels in thesubject. The 15-PGDH inhibitor can include a compound having formula(I):

-   -   wherein n is 0-2;    -   Y¹, Y², and R¹ are the same or different and are each selected        from the group consisting of hydrogen, substituted or        unsubstituted C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl,        C₃-C₂₀ aryl, heteroaryl, heterocycloalkenyl containing from 5-6        ring atoms (wherein from 1-3 of the ring atoms is independently        selected from N, NH, N(C₁-C₆ alkyl), NC(O) (C₁-C₆ alkyl), O, and        S), C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, halo, —Si(C₁-C₃ alkyl)₃,        hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄        alkynyloxy, C₅-C₂₀ aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl        (—CO-alkyl) and C₆-C₂₀ arylcarbonyl (—CO-aryl)), acyloxy        (—O-acyl), C₂-C₂₄ alkoxycarbonyl (—(CO)—O-alkyl), C₆-C₂₀        aryloxycarbonyl (—(CO)—O-aryl), C₂-C₂₄ alkylcarbonato        (—O—(CO)—O-alkyl), C₆-C₂₀ arylcarbonato (—O—(CO)—O-aryl),        carboxy (—COOH), carboxylato (—COO⁻), carbamoyl (—(CO)—NH₂),        C₁-C₂₄ alkyl-carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), arylcarbamoyl        (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH₂), carbamido        (—NH—(CO)—NH₂), cyano(—CN), isocyano (—N⁺C⁻), cyanato (—O—CN),        isocyanato (—O—N⁺═C⁻), isothiocyanato (—S—CN), azido (—N═N⁺═N⁻),        formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH₂), C₁-C₂₄        alkyl amino, C₅-C₂₀ aryl amino, C₂-C₂₄ alkylamido        (—NH—(CO)-alkyl), C₆-C₂₀ arylamido (—NH—(CO)-aryl), imino        (—CR═NH where R is hydrogen, C₁-C₂₄ alkyl, C₅-C₂₀ aryl, C₆-C₂₄        alkaryl, C₆-C₂₄ aralkyl, etc.), alkylimino (—CR═N(alkyl), where        R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino        (—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.),        nitro (—NO₂), nitroso (—NO), sulfo (—SO₂—OH), sulfonato        (—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl; also termed        “alkylthio”), arylsulfanyl (—S-aryl; also termed “arylthio”),        C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl        (—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀        arylsulfonyl (—SO₂-aryl), phosphono (—P(O)(OH)₂), phosphonato        (—P(O)(O⁻)₂), phosphinato (—P(O)(O⁻)), phospho (—PO₂), phosphino        (—PH₂), combinations thereof, and wherein Y¹ and Y² may be        linked to form a cyclic or polycyclic ring, wherein the ring is        a substituted or unsubstituted aryl, a substituted or        unsubstituted heteroaryl, a substituted or unsubstituted        cycloalkyl, and a substituted or unsubstituted heterocyclyl;    -   U¹ is N, C—R², or C—NR³R⁴, wherein R² is selected from the group        consisting of a H, a lower alkyl group, O, (CH₂)n₁OR′ (wherein        n1=1, 2, or 3), CF₃, CH₂—CH₂X, O—CH₂—CH₂X, CH₂—CH₂—CH₂X,        O—CH₂—CH₂X, X, (wherein X=H, F, Cl, Br, or I), CN, (C═O)—R′,        (C═O)N(R′)₂, O(CO)R′, COOR′ (wherein R′ is H or a lower alkyl        group), and wherein R¹ and R² may be linked to form a cyclic or        polycyclic ring, wherein R³ and R⁴ are same or different and are        each selected from the group consisting of H, a lower alkyl        group, O, (CH₂)_(n1)OR′ (wherein n1=1, 2, or 3), CF₃, CH₂—CH₂X,        CH₂—CH₂—CH₂X, (wherein X=H, F, Cl, Br, or I), CN, (C═O)—R′,        (C═O)N(R′)₂, COOR′ (wherein R′ is H or a lower alkyl group), and        R³ or R⁴ may be absent;    -   X¹ and X² are independently N or C, and wherein when X¹ and/or        X² are N, Y¹ and/or Y², respectively, are absent;    -   Z¹ is O, S, CR^(a)R^(b) or NR^(a), wherein R^(a) and R^(b) are        independently H or a C₁₋₈ alkyl, which is linear, branched, or        cyclic, and which is unsubstituted or substituted;    -   and pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PGDH inhibitor can include a compoundhaving the following formula (V):

-   -   wherein n is 0-2    -   X⁶ is independently is N or CR^(c)    -   R¹, R⁶, R⁷, and R^(c) are each independently selected from the        group consisting of hydrogen, substituted or unsubstituted        C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₃-C₂₀ aryl,        heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms        (wherein from 1-3 of the ring atoms is independently selected        from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S),        C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, halo, —Si(C₁-C₃ alkyl)₃,        hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄        alkynyloxy, C₅-C₂₀ aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl        (—CO-alkyl) and C₆-C₂₀ arylcarbonyl (—CO-aryl)), acyloxy        (—O-acyl), C₂-C₂₄ alkoxycarbonyl (—(CO)—O-alkyl), C₆-C₂₀        aryloxycarbonyl (—(CO)—O-aryl), C₂-C₂₄ alkylcarbonato        (—O—(CO)—O-alkyl), C₆-C₂₀ arylcarbonato (—O—(CO)—O-aryl),        carboxy (—COOH), carboxylato (—COO⁻), carbamoyl (—(CO)—NH₂),        C₁-C₂₄ alkyl-carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), arylcarbamoyl        (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH₂), carbamido        (—NH—(CO)—NH₂), cyano(—CN), isocyano (—N⁺C⁻), cyanato (—O—CN),        isocyanato (—O—N⁺═C⁻), isothiocyanato (—S—CN), azido (—N═N⁺═N⁻),        formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH₂), C₁-C₂₄        alkyl amino, C₅-C₂₀ aryl amino, C₂-C₂₄ alkylamido        (—NH—(CO)-alkyl), C₆-C₂₀ arylamido (—NH—(CO)-aryl), imino        (—CR═NH where R is hydrogen, C₁-C₂₄ alkyl, C₅-C₂₀ aryl, C₆-C₂₄        alkaryl, C₆-C₂₄ aralkyl, etc.), alkylimino (—CR═N(alkyl), where        R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino        (—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.),        nitro (—NO₂), nitroso (—NO), sulfo (—SO₂—OH), sulfonato        (—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl; also termed        “alkylthio”), arylsulfanyl (—S-aryl; also termed “arylthio”),        C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl        (—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀        arylsulfonyl (—SO₂-aryl), sulfonamide (—SO₂—NH2, —SO₂NY₂        (wherein Y is independently H, aryl or alkyl), phosphono        (—P(O)(OH)₂), phosphonato (—P(O)(O⁻)₂), phosphinato (—P(O)(O⁻)),        phospho (—PO₂), phosphino (—PH₂), polyalkylethers, phosphates,        phosphate esters, groups incorporating amino acids or other        moieties expected to bear positive or negative charge at        physiological pH, combinations thereof, and wherein R⁶ and R⁷        may be linked to form a cyclic or polycyclic ring, wherein the        ring is a substituted or unsubstituted aryl, a substituted or        unsubstituted heteroaryl, a substituted or unsubstituted        cycloalkyl, and a substituted or unsubstituted heterocyclyl;    -   U¹ is N, C—R², or C—NR³R⁴, wherein R² is selected from the group        consisting of a H, a lower alkyl group, O, (CH₂)_(n1)OR′        (wherein n1=1, 2, or 3), CF₃, CH₂—CH₂X, O—CH₂—CH₂X,        CH₂—CH₂—CH₂X, O—CH₂—CH₂X, X, (wherein X=H, F, Cl, Br, or I), CN,        (C═O)—R′, (C═O)N(R′)₂, O(CO)R′, COOR′ (wherein R′ is H or a        lower alkyl group), and wherein R¹ and R² may be linked to form        a cyclic or polycyclic ring, wherein R³ and R⁴ are the same or        different and are each selected from the group consisting of H,        a lower alkyl group, O, (CH₂)_(n1)OR′ (wherein n1=1, 2, or 3),        CF₃, CH₂—CH₂X, CH₂—CH₂—CH₂X, (wherein X=H, F, Cl, Br, or I), CN,        (C═O)—R′, (C═O)N(R′)₂, COOR′ (wherein R′ is H or a lower alkyl        group), and R³ or R⁴ may be absent;    -   and pharmaceutically acceptable salts thereof.

In some embodiments, R¹ is selected from the group consisting ofbranched or linear alkyl including —(CH₂)n₁CH₃ (n₁=0-7),

wherein n₂=0-6 and X is any of the following: CF_(y)H_(z) (y+z=3),CCl_(y)H_(z) (y+z=3), OH, OAc, OMe, R⁷¹, OR⁷², CN, N(R⁷³)₂,

(n₃=0-5, m=1-5), and

(n₄=0-5).

In other embodiments, R⁶ and R⁷ can each independently be one of thefollowing:

each R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵,R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹,R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³,R⁶⁴, R⁶⁵, R⁶⁶, R⁶⁷, R⁶⁸, R⁶⁹, R⁷⁰, R⁷¹, R⁷², R⁷³, and R⁷⁴, are the sameor different and are independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl,C₂-C₂₄ alkynyl, C₃-C₂₀ aryl, heterocycloalkenyl containing from 5-6 ringatoms, (wherein from 1-3 of the ring atoms is independently selectedfrom N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S), heteroaryl orheterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of thering atoms is independently selected from N, NH, N(C₁-C₃ alkyl), O, andS), C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, halo, silyl, hydroxyl, sulfhydryl,C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₀ aryloxy,acyl (including C₂-C₂₄ alkylcarbonyl (—CO-alkyl) and C₆-C₂₀ arylcarbonyl(—CO-aryl)), acyloxy (—O-acyl), C₂-C₂₄ alkoxycarbonyl (—(CO)—O-alkyl),C₆-C₂₀ aryloxycarbonyl (—(CO)—O-aryl), C₂-C₂₄ alkylcarbonato(—O—(CO)—O-alkyl), C₆-C₂₀ arylcarbonato (—O—(CO)—O-aryl), carboxy(—COOH), carboxylato (—COO⁻), carbamoyl (—(CO)—NH₂), C₁-C₂₄alkyl-carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), arylcarbamoyl (—(CO)—NH-aryl),thiocarbamoyl (—(CS)—NH₂), carbamido (—NH—(CO)—NH₂), cyano(—CN),isocyano (—N⁺C⁻), cyanato (—O—CN), isocyanato (—O—N⁺═C⁻), isothiocyanato(—S—CN), azido (—N═N⁺═N⁻), formyl (—(CO)—H), thioformyl (—(CS)—H), amino(—NH₂), C₁-C₂₄ alkyl amino, C₅-C₂₀ aryl amino, C₂-C₂₄ alkylamido(—NH—(CO)-alkyl), C₆-C₂₀ arylamido (—NH—(CO)-aryl), sulfanamido(—SO₂N(R)₂ where R is independently H, alkyl, aryl or heteroaryl), imino(—CR═NH where R is hydrogen, C₁-C₂₄ alkyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl,C₆-C₂₄ aralkyl, etc.), alkylimino (—CR═N(alkyl), where R=hydrogen,alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR═N(aryl), whereR=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO₂), nitroso (—NO),sulfo (—SO₂—OH), sulfonato (—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl;also termed “alkylthio”), arylsulfanyl (—S-aryl; also termed“arylthio”), C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl(—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀ arylsulfonyl(—SO₂-aryl), sulfonamide (—SO₂—NH₂, —SO₂NY₂ (wherein Y is independentlyH, aryl or alkyl), phosphono (—P(O)(OH)₂), phosphonato (—P(O)(O⁻)₂),phosphinato (—P(O)(O⁻)), phospho (—PO₂), phosphino (—PH₂), polyalkylethers (—[(CH₂)_(n)O]_(m)), phosphates, phosphate esters [—OP(O)(OR)₂where R=H, methyl or other alkyl], groups incorporating amino acids orother moieties expected to bear positive or negative charge atphysiological pH, and combinations thereof, and pharmaceuticallyacceptable salts thereof.

In some embodiments, the 15-PGDH inhibitor can inhibit the enzymaticactivity of recombinant 15-PGDH at an IC₅₀ of less than 1 μM, orpreferably at an IC₅₀ of less than 250 nM, or more preferably at an IC₅₀of less than 50 nM, or more preferably at an IC₅₀ of less than 10 nM, ormore preferably at an IC₅₀ of less than 5 nM at a recombinant 15-PGDHconcentration of about 5 nM to about 10 nM.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates schematically the design of a study in which maleC57bl6J mice received 15 mpk cumulative dose of doxorubicin in 7 dosesof 2.15 mpk administered daily over study days 1-7. Cardiac ejectionfraction was determined by echocardiography on study days 14 and 28.

FIG. 2 illustrates a graph showing cardiac ejection fraction at studyday 1, at the start of the experiment, at study day 14 and at study day28 of control mice receiving either oral saline or oral vehicle,doxorubicin treated mice receiving oral vehicle, doxorubicin treatedmice also receiving (+) SW033291.

FIG. 3 illustrates representative echocardiograms on study day 14 ofdoxorubicin treated mice receiving either oral vehicle (upper panel) ororal (+) SW033291 (lower panel).

FIG. 4 illustrates induction of DNA damage in cardiac myocytes ofdoxorubicin treated mice as visualized by immunostaining for gamma-H2AX.

FIG. 5 illustrates images and graphs showing that doxorubicin inducesequal levels of DNA damage in mice receiving oral (+) SW033291 as inmice receiving oral vehicle, as assayed by gamma-H2AX immunostaining.

FIG. 6 illustrates schematically the design of a second follow on study(Set B) in which mice were treated with 2 consecutive cycles ofdoxorubicin.

FIG. 7 graphs showing the results for the ejection fraction (EF %) ofthe first cohort of mice (Set A) graphed in FIG. 2 , but with follow-upnow extended to day 56.

FIG. 8 illustrates a plot and graph showing ventricular weight and lungweight of mice from Set B treated with two cycles of two cycles ofdoxorubicin and (+)-SW033291 or control vehicle.

FIG. 9 illustrates graph showing atrial natriuretic factor (as measuredby real-time PCR in cardiac tissue) of mice from Set B treated with twocycles of two cycles of doxorubicin and (+)-SW033291 or control vehicle.

FIG. 10 illustrates a graph showing levels of expression of connectivetissue growth factor (as measured by real-time PCR in cardiac tissue) ofmice from Set B treated with two cycles of doxorubicin and (+)-SW033291or control vehicle.

FIG. 11 illustrates graphs showing activity of cardiac 15-PGDH andcardiac PGE2 of mice treated with cardiac PGE2 with (+)-SW033291.

DETAILED DESCRIPTION

For convenience, certain terms employed in the specification, examples,and appended claims are collected here. Unless defined otherwise, alltechnical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisapplication belongs.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The terms “comprise,” “comprising,” “include,” “including,” “have,” and“having” are used in the inclusive, open sense, meaning that additionalelements may be included. The terms “such as”, “e.g.”, as used hereinare non-limiting and are for illustrative purposes only. “Including” and“including but not limited to” are used interchangeably.

The term “or” as used herein should be understood to mean “and/or”,unless the context clearly indicates otherwise.

As used herein, the term “about” or “approximately” refers to aquantity, level, value, number, frequency, percentage, dimension, size,amount, weight or length that varies by as much as 15%, 10%, 9%, 8%, 7%,6%, 5%, 4%, 3%, 2% or 1% to a reference quantity, level, value, number,frequency, percentage, dimension, size, amount, weight or length. In oneembodiment, the term “about” or “approximately” refers a range ofquantity, level, value, number, frequency, percentage, dimension, size,amount, weight or length ±15%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%,±2%, or ±1% about a reference quantity, level, value, number, frequency,percentage, dimension, size, amount, weight or length.

It will be noted that the structure of some of the compounds of theapplication include asymmetric (chiral) carbon or sulfur atoms. It is tobe understood accordingly that the isomers arising from such asymmetryare included herein, unless indicated otherwise. Such isomers can beobtained in substantially pure form by classical separation techniquesand by stereochemically controlled synthesis. The compounds of thisapplication may exist in stereoisomeric form, therefore can be producedas individual stereoisomers or as mixtures.

The term “isomerism” means compounds that have identical molecularformulae but that differ in the nature or the sequence of bonding oftheir atoms or in the arrangement of their atoms in space. Isomers thatdiffer in the arrangement of their atoms in space are termed“stereoisomers”. Stereoisomers that are not mirror images of one anotherare termed “diastereoisomers”, and stereoisomers that arenon-superimposable mirror images are termed “enantiomers”, or sometimesoptical isomers. A carbon atom bonded to four nonidentical substituentsis termed a “chiral center” whereas a sulfur bound to three or fourdifferent substitutents, e.g. sulfoxides or sulfinimides, is likewisetermed a “chiral center”.

The term “chiral isomer” means a compound with at least one chiralcenter. It has two enantiomeric forms of opposite chirality and mayexist either as an individual enantiomer or as a mixture of enantiomers.A mixture containing equal amounts of individual enantiomeric forms ofopposite chirality is termed a “racemic mixture”. A compound that hasmore than one chiral center has 2n−1 enantiomeric pairs, where n is thenumber of chiral centers. Compounds with more than one chiral center mayexist as either an individual diastereomer or as a mixture ofdiastereomers, termed a “diastereomeric mixture”. When one chiral centeris present, a stereoisomer may be characterized by the absoluteconfiguration (R or S) of that chiral center. Alternatively, when one ormore chiral centers are present, a stereoisomer may be characterized as(+) or (−). Absolute configuration refers to the arrangement in space ofthe substituents attached to the chiral center. The substituentsattached to the chiral center under consideration are ranked inaccordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn etal, Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al.,Angew. Chem. 1966, 78, 413; Cahn and Ingold, J Chem. Soc. 1951 (London),612; Cahn et al., Experientia 1956, 12, 81; Cahn, J., Chem. Educ. 1964,41, 116).

The term “geometric Isomers” means the diastereomers that owe theirexistence to hindered rotation about double bonds. These configurationsare differentiated in their names by the prefixes cis and trans, or Zand E, which indicate that the groups are on the same or opposite sideof the double bond in the molecule according to the Cahn-Ingold-Prelogrules. Further, the structures and other compounds discussed in thisapplication include all atropic isomers thereof.

The term “atropic isomers” are a type of stereoisomer in which the atomsof two isomers are arranged differently in space. Atropic isomers owetheir existence to a restricted rotation caused by hindrance of rotationof large groups about a central bond. Such atropic isomers typicallyexist as a mixture, however as a result of recent advances inchromatography techniques, it has been possible to separate mixtures oftwo atropic isomers in select cases.

The terms “crystal polymorphs” or “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or salt or solvate thereof) cancrystallize in different crystal packing arrangements, all of which havethe same elemental composition. Different crystal forms usually havedifferent X-ray diffraction patterns, infrared spectral, melting points,density hardness, crystal shape, optical and electrical properties,stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Crystal polymorphs of the compounds can beprepared by crystallization under different conditions.

The term “derivative” refers to compounds that have a common corestructure, and are substituted with various groups as described herein.

The term “bioisostere” refers to a compound resulting from the exchangeof an atom or of a group of atoms with another, broadly similar, atom orgroup of atoms. The objective of a bioisosteric replacement is to createa new compound with similar biological properties to the parentcompound. The bioisosteric replacement may be physicochemically ortopologically based. Examples of carboxylic acid bioisosteres includeacyl sulfonimides, tetrazoles, sulfonates, and phosphonates. See, e.g.,Patani and LaVoie, Chem. Rev. 96, 3147-3176 (1996).

The phrases “parenteral administration” and “administered parenterally”are art-recognized terms, and include modes of administration other thanenteral and topical administration, such as injections, and include,without limitation, intravenous, intramuscular, intrapleural,intravascular, intrapericardial, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular,subarachnoid, intraspinal and intrastemal injection and infusion.

The term “treating” is art-recognized and includes inhibiting a disease,disorder or condition in a subject, e.g., impeding its progress; andrelieving the disease, disorder or condition, e.g., causing regressionof the disease, disorder and/or condition. Treating the disease orcondition includes ameliorating at least one symptom of the particulardisease or condition, even if the underlying pathophysiology is notaffected. For example, the term “treating” can refer to theadministration of a short chain dehydrogenase inhibitor (e.g., 15-PGDHinhibitor) to slow or inhibit the progression of congestive heartfailure during the treatment, relative to the disease progression thatwould occur in the absence of treatment, in a statistically significantmanner. Well known indicia such as left ventricular ejection fraction,exercise performance, and other clinical tests as enumerated below, aswell as survival rates and hospitalization rates may be used to assessdisease progression. Whether or not a treatment slows or inhibitsdisease progression in a statistically significant manner may bedetermined by methods that are well known in the art.

The term “preventing” is art-recognized and includes stopping a disease,disorder or condition from occurring in a subject, which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it. Preventing a condition related to a diseaseincludes stopping the condition from occurring after the disease hasbeen diagnosed but before the condition has been diagnosed. For example,the term “preventing” can refer to minimizing or partially or completelyinhibiting the development of congestive heart failure in a mammal atrisk for developing congestive heart failure (as defined in “Consensusrecommendations for the management of chronic heart failure.” Am. J.Cardiol., 83(2A):1A-38-A, 1999).

The term “pharmaceutical composition” refers to a formulation containingthe disclosed compounds in a form suitable for administration to asubject. In a preferred embodiment, the pharmaceutical composition is inbulk or in unit dosage form. The unit dosage form is any of a variety offorms, including, for example, a capsule, an IV bag, a tablet, a singlepump on an aerosol inhaler, or a vial. The quantity of active ingredient(e.g., a formulation of the disclosed compound or salts thereof) in aunit dose of composition is an effective amount and is varied accordingto the particular treatment involved. One skilled in the art willappreciate that it is sometimes necessary to make routine variations tothe dosage depending on the age and condition of the patient. The dosagewill also depend on the route of administration. A variety of routes arecontemplated, including oral, pulmonary, rectal, parenteral,transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal,intranasal, inhalational, and the like. Dosage forms for the topical ortransdermal administration of a compound described herein includespowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches, nebulized compounds, and inhalants. In a preferred embodiment,the active compound is mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that are required.

The term “flash dose” refers to compound formulations that are rapidlydispersing dosage forms.

The term “immediate release” is defined as a release of compound from adosage form in a relatively brief period of time, generally up to about60 minutes. The term “modified release” is defined to include delayedrelease, extended release, and pulsed release. The term “pulsed release”is defined as a series of releases of drug from a dosage form. The term“sustained release” or “extended release” is defined as continuousrelease of a compound from a dosage form over a prolonged period.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, polymers and othermaterials and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized, andincludes, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting any subject composition from one organ, or portion of thebody, to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof a subject composition and not injurious to the patient. In certainembodiments, a pharmaceutically acceptable carrier is non-pyrogenic.Some examples of materials which may serve as pharmaceuticallyacceptable carriers include: (1) sugars, such as lactose, glucose andsucrose; (2) starches, such as corn starch and potato starch; (3)cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5)malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter andsuppository waxes; (9) oils, such as peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10)glycols, such as propylene glycol; (11) polyols, such as glycerin,sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyloleate and ethyl laurate; (13) agar; (14) buffering agents, such asmagnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19)ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxiccompatible substances employed in pharmaceutical formulations.

The compounds of the application are capable of further forming salts.All of these forms are also contemplated herein.

“Pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. For example, the saltcan be an acid addition salt. One embodiment of an acid addition salt isa hydrochloride salt. The pharmaceutically acceptable salts can besynthesized from a parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrilebeing preferred. Lists of salts are found in Remington's PharmaceuticalSciences, 18th ed. (Mack Publishing Company, 1990).

The compounds described herein can also be prepared as esters, forexample pharmaceutically acceptable esters. For example, a carboxylicacid function group in a compound can be converted to its correspondingester, e.g., a methyl, ethyl, or other ester. Also, an alcohol group ina compound can be converted to its corresponding ester, e.g., anacetate, propionate, or other ester.

The compounds described herein can also be prepared as prodrugs, forexample pharmaceutically acceptable prodrugs. The terms “pro-drug” and“prodrug” are used interchangeably herein and refer to any compound,which releases an active parent drug in vivo. Since prodrugs are knownto enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds can bedelivered in prodrug form. Thus, the compounds described herein areintended to cover prodrugs of the presently claimed compounds, methodsof delivering the same and compositions containing the same. “Prodrugs”are intended to include any covalently bonded carriers that release anactive parent drug in vivo when such prodrug is administered to asubject. Prodrugs are prepared by modifying functional groups present inthe compound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound. Prodrugsinclude compounds wherein a hydroxy, amino, sulfhydryl, carboxy, orcarbonyl group is bonded to any group that may be cleaved in vivo toform a free hydroxyl, free amino, free sulfhydryl, free carboxy or freecarbonyl group, respectively. Prodrugs can also include a precursor(forerunner) of a compound described herein that undergoes chemicalconversion by metabolic processes before becoming an active or moreactive pharmacological agent or active compound described herein.

Examples of prodrugs include, but are not limited to, esters (e.g.,acetate, dialkylaminoacetates, formates, phosphates, sulfates, andbenzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl)of hydroxy functional groups, ester groups (e.g., ethyl esters,morpholinoethanol esters) of carboxyl functional groups, N-acylderivatives (e.g., N-acetyl)N-Mannich bases, Schiff bases and enaminonesof amino functional groups, oximes, acetals, ketals and enol esters ofketone and aldehyde functional groups in compounds, and the like, aswell as sulfides that are oxidized to form sulfoxides or sulfones.

The term “protecting group” refers to a grouping of atoms that whenattached to a reactive group in a molecule masks, reduces or preventsthat reactivity. Examples of protecting groups can be found in Green andWuts, Protective Groups in Organic Chemistry, (Wiley, 2.sup.nd ed.1991); Harrison and Harrison et al., Compendium of Synthetic OrganicMethods, Vols. 1-8 (John Wiley and Sons, 1971-1996); and Kocienski,Protecting Groups, (Verlag, 3^(rd) ed. 2003).

The term “amine protecting group” is intended to mean a functional groupthat converts an amine, amide, or other nitrogen-containing moiety intoa different chemical group that is substantially inert to the conditionsof a particular chemical reaction. Amine protecting groups arepreferably removed easily and selectively in good yield under conditionsthat do not affect other functional groups of the molecule. Examples ofamine protecting groups include, but are not limited to, formyl, acetyl,benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, t-butyloxycarbonyl(Boc), p-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl,trimethylsilyl (TMS), fluorenyl-methyloxycarbonyl,2-trimethylsilyl-ethyoxycarbonyl, 1-methyl-1-(4-biphenylyl)ethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl (CBZ),2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted tritylgroups, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl(NVOC), and the like. Those of skill in the art can identify othersuitable amine protecting groups.

Representative hydroxy protecting groups include those where the hydroxygroup is either acylated or alkylated such as benzyl, and trityl ethersas well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethersand allyl ethers.

Additionally, the salts of the compounds described herein, can exist ineither hydrated or unhydrated (the anhydrous) form or as solvates withother solvent molecules. Non-limiting examples of hydrates includemonohydrates, dihydrates, etc. Nonlimiting examples of solvates includeethanol solvates, acetone solvates, etc.

The term “solvates” means solvent addition forms that contain eitherstoichiometric or non-stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

The compounds, salts and prodrugs described herein can exist in severaltautomeric forms, including the enol and imine form, and the keto andenamine form and geometric isomers and mixtures thereof. Tautomers existas mixtures of a tautomeric set in solution. In solid form, usually onetautomer predominates. Even though one tautomer may be described, thepresent application includes all tautomers of the present compounds. Atautomer is one of two or more structural isomers that exist inequilibrium and are readily converted from one isomeric form to another.This reaction results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Insolutions where tautomerization is possible, a chemical equilibrium ofthe tautomers will be reached. The exact ratio of the tautomers dependson several factors, including temperature, solvent, and pH. The conceptof tautomers that are interconvertable by tautomerizations is calledtautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs.

Tautomerizations can be catalyzed by: Base: 1. deprotonation; 2.formation of a delocalized anion (e.g., an enolate); 3. protonation at adifferent position of the anion; Acid: 1. protonation; 2. formation of adelocalized cation; 3. deprotonation at a different position adjacent tothe cation.

The term “analogue” refers to a chemical compound that is structurallysimilar to another but differs slightly in composition (as in thereplacement of one atom by an atom of a different element or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analogue is acompound that is similar or comparable in function and appearance, butnot in structure or origin to the reference compound.

A “patient,” “subject,” or “host” to be treated by the subject methodmay mean either a human or non-human animal, such as a mammal, a fish, abird, a reptile, or an amphibian. Thus, the subject of the hereindisclosed methods can be a human, non-human primate, horse, pig, rabbit,dog, sheep, goat, cow, cat, guinea pig or rodent. The term does notdenote a particular age or sex. Thus, adult and newborn subjects, aswell as fetuses, whether male or female, are intended to be covered. Inone aspect, the subject is a mammal. A patient refers to a subjectafflicted with a disease or disorder.

The terms “prophylactic” and “therapeutic” treatment is art-recognizedand includes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, i.e., it protects thehost against developing the unwanted condition, whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The terms “therapeutic agent”, “drug”, “medicament” and “bioactivesubstance” are art-recognized and include molecules and other agentsthat are biologically, physiologically, or pharmacologically activesubstances that act locally or systemically in a patient or subject totreat a disease or condition. The terms include without limitationpharmaceutically acceptable salts thereof and prodrugs. Such agents maybe acidic, basic, or salts; they may be neutral molecules, polarmolecules, or molecular complexes capable of hydrogen bonding; they maybe prodrugs in the form of ethers, esters, amides and the like that arebiologically activated when administered into a patient or subject.

The terms “therapeutically effective amount” and “pharmaceuticallyeffective amount” are an art-recognized term. In certain embodiments,the term refers to an amount of a therapeutic agent that produces somedesired effect at a reasonable benefit/risk ratio applicable to anymedical treatment. In certain embodiments, the term refers to thatamount necessary or sufficient to eliminate, reduce or maintain a targetof a particular therapeutic regimen. The effective amount may varydepending on such factors as the disease or condition being treated, theparticular targeted constructs being administered, the size of thesubject or the severity of the disease or condition. One of ordinaryskill in the art may empirically determine the effective amount of aparticular compound without necessitating undue experimentation. Incertain embodiments, a therapeutically effective amount of a therapeuticagent for in vivo use will likely depend on a number of factors,including: the rate of release of an agent from a polymer matrix, whichwill depend in part on the chemical and physical characteristics of thepolymer; the identity of the agent; the mode and method ofadministration; and any other materials incorporated in the polymermatrix in addition to the agent.

The term “ED50” is art-recognized. In certain embodiments, ED50 meansthe dose of a drug, which produces 50% of its maximum response oreffect, or alternatively, the dose, which produces a pre-determinedresponse in 50% of test subjects or preparations. The term “LD50” isart-recognized. In certain embodiments, LD50 means the dose of a drug,which is lethal in 50% of test subjects. The term “therapeutic index” isan art-recognized term, which refers to the therapeutic index of a drug,defined as LD50/ED50.

The terms “IC₅₀,” or “half maximal inhibitory concentration” is intendedto refer to the concentration of a substance (e.g., a compound or adrug) that is required for 50% inhibition of a biological process, orcomponent of a process, including a protein, subunit, organelle,ribonucleoprotein, etc.

With respect to any chemical compounds, the present application isintended to include all isotopes of atoms occurring in the presentcompounds. Isotopes include those atoms having the same atomic numberbut different mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium, andisotopes of carbon include C-13 and C-14.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent can be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent can be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

When an atom or a chemical moiety is followed by a subscripted numericrange (e.g., C₁₋₆), it is meant to encompass each number within therange as well as all intermediate ranges. For example, “C₁₋₆ alkyl” ismeant to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4, 1-3,1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.

The term “alkyl” is intended to include both branched (e.g., isopropyl,tert-butyl, isobutyl), straight-chain e.g., methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), and cycloalkyl(e.g., alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl groups. Such aliphatic hydrocarbon groupshave a specified number of carbon atoms. For example, C₁₋₆ alkyl isintended to include Cl, C₂, C₃, C₄, C₅, and C₆ alkyl groups. As usedherein, “lower alkyl” refers to alkyl groups having from 1 to 6 carbonatoms in the backbone of the carbon chain. “Alkyl” further includesalkyl groups that have oxygen, nitrogen, sulfur or phosphorous atomsreplacing one or more hydrocarbon backbone carbon atoms. In certainembodiments, a straight chain or branched chain alkyl has six or fewercarbon atoms in its backbone (e.g., C₁-C₆ for straight chain, C₃-C₆ forbranched chain), for example four or fewer. Likewise, certaincycloalkyls have from three to eight carbon atoms in their ringstructure, such as five or six carbons in the ring structure.

The term “substituted alkyls” refers to alkyl moieties havingsubstituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkyl,alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.,with the substituents described above. An “alkylaryl” or an “aralkyl”moiety is an alkyl substituted with an aryl (e.g., phenylmethyl(benzyl)). If not otherwise indicated, the terms “alkyl” and “loweralkyl” include linear, branched, cyclic, unsubstituted, substituted,and/or heteroatom-containing alkyl or lower alkyl, respectively.

The term “alkenyl” refers to a linear, branched or cyclic hydrocarbongroup of 2 to about 24 carbon atoms containing at least one double bond,such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl,octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl,cyclopentenyl, cyclohexenyl, cyclooctenyl, and the like. Generally,although again not necessarily, alkenyl groups can contain 2 to about 18carbon atoms, and more particularly 2 to 12 carbon atoms. The term“lower alkenyl” refers to an alkenyl group of 2 to 6 carbon atoms, andthe specific term “cycloalkenyl” intends a cyclic alkenyl group,preferably having 5 to 8 carbon atoms. The term “substituted alkenyl”refers to alkenyl substituted with one or more substituent groups, andthe terms “heteroatom-containing alkenyl” and “heteroalkenyl” refer toalkenyl or heterocycloalkenyl (e.g., heterocylcohexenyl) in which atleast one carbon atom is replaced with a heteroatom. If not otherwiseindicated, the terms “alkenyl” and “lower alkenyl” include linear,branched, cyclic, unsubstituted, substituted, and/orheteroatom-containing alkenyl and lower alkenyl, respectively.

The term “alkynyl” refers to a linear or branched hydrocarbon group of 2to 24 carbon atoms containing at least one triple bond, such as ethynyl,n-propynyl, and the like. Generally, although again not necessarily,alkynyl groups can contain 2 to about 18 carbon atoms, and moreparticularly can contain 2 to 12 carbon atoms. The term “lower alkynyl”intends an alkynyl group of 2 to 6 carbon atoms. The term “substitutedalkynyl” refers to alkynyl substituted with one or more substituentgroups, and the terms “heteroatom-containing alkynyl” and“heteroalkynyl” refer to alkynyl in which at least one carbon atom isreplaced with a heteroatom. If not otherwise indicated, the terms“alkynyl” and “lower alkynyl” include linear, branched, unsubstituted,substituted, and/or heteroatom-containing alkynyl and lower alkynyl,respectively.

The terms “alkyl”, “alkenyl”, and “alkynyl” are intended to includemoieties which are diradicals, i.e., having two points of attachment. Anonlimiting example of such an alkyl moiety that is a diradical is—CH₂CH₂—, i.e., a C₂ alkyl group that is covalently bonded via eachterminal carbon atom to the remainder of the molecule.

The term “alkoxy” refers to an alkyl group bound through a single,terminal ether linkage; that is, an “alkoxy” group may be represented as—O-alkyl where alkyl is as defined above. A “lower alkoxy” group intendsan alkoxy group containing 1 to 6 carbon atoms, and includes, forexample, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, etc.Preferred substituents identified as “C₁-C₆ alkoxy” or “lower alkoxy”herein contain 1 to 3 carbon atoms, and particularly preferred suchsubstituents contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

The term “aryl” refers to an aromatic substituent containing a singlearomatic ring or multiple aromatic rings that are fused together,directly linked, or indirectly linked (such that the different aromaticrings are bound to a common group such as a methylene or ethylenemoiety). Aryl groups can contain 5 to 20 carbon atoms, and particularlypreferred aryl groups can contain 5 to 14 carbon atoms. Examples of arylgroups include benzene, phenyl, pyrrole, furan, thiophene, thiazole,isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole,isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and thelike. Furthermore, the term “aryl” includes multicyclic aryl groups,e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole,benzodioxazole, benzothiazole, benzoimidazole, benzothiophene,methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole,benzofuran, purine, benzofuran, deazapurine, or indolizine. Those arylgroups having heteroatoms in the ring structure may also be referred toas “aryl heterocycles”, “heterocycles,” “heteroaryls” or“heteroaromatics”. The aromatic ring can be substituted at one or morering positions with such substituents as described above, as forexample, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diaryl amino, and al kylaryl amino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Aryl groups can also be fused or bridged withalicyclic or heterocyclic rings, which are not aromatic so as to form amulticyclic system (e.g., tetralin, methylenedioxyphenyl). If nototherwise indicated, the term “aryl” includes unsubstituted,substituted, and/or heteroatom-containing aromatic substituents.

The term “alkaryl” refers to an aryl group with an alkyl substituent,and the term “aralkyl” refers to an alkyl group with an arylsubstituent, wherein “aryl” and “alkyl” are as defined above. Exemplaryaralkyl groups contain 6 to 24 carbon atoms, and particularly preferredaralkyl groups contain 6 to 16 carbon atoms. Examples of aralkyl groupsinclude, without limitation, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl,4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl,4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like.Alkaryl groups include, for example, p-methylphenyl, 2,4-dimethylphenyl,p-cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctylnaphthyl,3-ethyl-cyclopenta-1,4-diene, and the like.

The terms “heterocyclyl” and “heterocyclic group” include closed ringstructures, e.g., 3- to 10-, or 4- to 7-membered rings, which includeone or more heteroatoms. “Heteroatom” includes atoms of any elementother than carbon or hydrogen. Examples of heteroatoms include nitrogen,oxygen, sulfur and phosphorus.

Heterocyclyl groups can be saturated or unsaturated and includepyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine,lactones, lactams, such as azetidinones and pyrrolidinones, sultams, andsultones. Heterocyclic groups such as pyrrole and furan can havearomatic character. They include fused ring structures, such asquinoline and isoquinoline. Other examples of heterocyclic groupsinclude pyridine and purine. The heterocyclic ring can be substituted atone or more positions with such substituents as described above, as forexample, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl,cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety.Heterocyclic groups can also be substituted at one or more constituentatoms with, for example, a lower alkyl, a lower alkenyl, a lower alkoxy,a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, ahydroxyl, —CF₃, or —CN, or the like.

The terms “halo” and “halogen” refers to fluoro, chloro, bromo, andiodo. “Counterion” is used to represent a small, negatively chargedspecies such as fluoride, chloride, bromide, iodide, hydroxide, acetate,and sulfate. The term sulfoxide refers to a sulfur attached to 2different carbon atoms and one oxygen and the S—O bond can begraphically represented with a double bond (S═O), a single bond withoutcharges (S—O) or a single bond with charges [S(+)−O(−)].

The term “substituted” as in “substituted alkyl”, “substituted aryl”,and the like, as alluded to in some of the aforementioned definitions,is meant that in the alkyl, aryl, or other moiety, at least one hydrogenatom bound to a carbon (or other) atom is replaced with one or morenon-hydrogen substituents. Examples of such substituents include,without limitation: functional groups such as halo, hydroxyl, silyl,sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₀aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl (—CO-alkyl) and C₆-C₂₀arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl), C₂-C₂₄ alkoxycarbonyl(—(CO)—O-alkyl), C₆-C₂₀ aryloxycarbonyl (—(CO)—O-aryl), C₂-C₂₄alkylcarbonato (—O—(CO)—O-alkyl), C₆-C₂₀ arylcarbonato (—O—(CO)—O-aryl),carboxy (—COOH), carboxylato (—COO⁻), carbamoyl (—(CO)—NH₂),mono-(C₁-C₂₄ alkyl)-substituted carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)),di-(C₁-C₄ alkyl)-substituted carbamoyl (—(CO)—N(C₁-C₂₄ alkyl)₂),mono-substituted arylcarbamoyl (—(CO)—NH-aryl), thiocarbamoyl(—(CS)—NH₂), carbamido (—NH—(CO)—NH₂), cyano(—CN), isocyano (—N⁺C⁻),cyanato (—O—CN), isocyanato (—ON⁺C⁻), isothiocyanato (—S—CN), azido(—N═N⁺═N⁻), formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH₂), mono-and di-(C₁-C₂₄ alkyl)-substituted amino, mono- and di-(C₅-C₂₀aryl)-substituted amino, C₂-C₂₄ alkylamido (—NH—(CO)-alkyl), C₆-C₂₀arylamido (—NH—(CO)-aryl), imino (—CR═NH where R=hydrogen, C₁-C₂₄ alkyl,C₅-C₂₀ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.), alkylimino(—CR═N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), arylimino(—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro(—NO₂), nitroso (—NO), sulfo (—SO₂—OH), sulfonato (—SO₂—O⁻), C₁-C₂₄alkylsulfanyl (—S-alkyl; also termed “alkylthio”), arylsulfanyl(—S-aryl; also termed “arylthio”), C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl),C₅-C₂₀ arylsulfinyl (—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl),C₅-C₂₀ arylsulfonyl (—SO₂-aryl), phosphono (—P(O)(OH)₂), phosphonato(—P(O)(O⁻)₂), phosphinato (—P(O)(O⁻)), phospho (—PO₂), and phosphino(—PH₂); and the hydrocarbyl moieties C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl,C₂-C₂₄ alkynyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl, and C₆-C₂₄ aralkyl.

In addition, the aforementioned functional groups may, if a particulargroup permits, be further substituted with one or more additionalfunctional groups or with one or more hydrocarbyl moieties such as thosespecifically enumerated above. Analogously, the above-mentionedhydrocarbyl moieties may be further substituted with one or morefunctional groups or additional hydrocarbyl moieties such as thosespecifically enumerated.

When the term “substituted” appears prior to a list of possiblesubstituted groups, it is intended that the term apply to every memberof that group. For example, the phrase “substituted alkyl, alkenyl, andaryl” is to be interpreted as “substituted alkyl, substituted alkenyl,and substituted aryl.” Analogously, when the term“heteroatom-containing” appears prior to a list of possibleheteroatom-containing groups, it is intended that the term apply toevery member of that group. For example, the phrase“heteroatom-containing alkyl, alkenyl, and aryl” is to be interpreted as“heteroatom-containing alkyl, substituted alkenyl, and substituted aryl.

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.For example, the phrase “optionally substituted” means that anon-hydrogen substituent may or may not be present on a given atom, and,thus, the description includes structures wherein a non-hydrogensubstituent is present and structures wherein a non-hydrogen substituentis not present.

The terms “stable compound” and “stable structure” are meant to indicatea compound that is sufficiently robust to survive isolation, and asappropriate, purification from a reaction mixture, and formulation intoan efficacious therapeutic agent.

The term “free compound” is used herein to describe a compound in theunbound state.

Throughout the description, where compositions are described as having,including, or comprising, specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where methods or processes are described ashaving, including, or comprising specific process steps, the processesalso consist essentially of, or consist of, the recited processingsteps. Further, it should be understood that the order of steps or orderfor performing certain actions is immaterial so long as the compositionsand methods described herein remains operable. Moreover, two or moresteps or actions can be conducted simultaneously.

The term “small molecule” is an art-recognized term. In certainembodiments, this term refers to a molecule, which has a molecularweight of less than about 2000 amu, or less than about 1000 amu, andeven less than about 500 amu.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

The terms “gene expression” and “protein expression” include anyinformation pertaining to the amount of gene transcript or proteinpresent in a sample, as well as information about the rate at whichgenes or proteins are produced or are accumulating or being degraded(e.g., reporter gene data, data from nuclear runoff experiments,pulse-chase data etc.). Certain kinds of data might be viewed asrelating to both gene and protein expression. For example, proteinlevels in a cell are reflective of the level of protein as well as thelevel of transcription, and such data is intended to be included by thephrase “gene or protein expression information”. Such information may begiven in the form of amounts per cell, amounts relative to a controlgene or protein, in unitless measures, etc.; the term “information” isnot to be limited to any particular means of representation and isintended to mean any representation that provides relevant information.The term “expression levels” refers to a quantity reflected in orderivable from the gene or protein expression data, whether the data isdirected to gene transcript accumulation or protein accumulation orprotein synthesis rates, etc.

The terms “healthy” and “normal” are used interchangeably herein torefer to a subject or particular cell or tissue that is devoid (at leastto the limit of detection) of a disease condition.

The term “nucleic acid” refers to polynucleotides such asdeoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid(RNA). The term should also be understood to include analogues of eitherRNA or DNA made from nucleotide analogues, and, as applicable to theembodiment being described, single-stranded (such as sense or antisense)and double-stranded polynucleotides. In some embodiments, “nucleic acid”refers to inhibitory nucleic acids. Some categories of inhibitorynucleic acid compounds include antisense nucleic acids, RNAi constructs,and catalytic nucleic acid constructs. Such categories of nucleic acidsare well-known in the art.

The term “congestive heart failure” refers to impaired cardiac functionthat renders the heart unable to maintain the normal blood output atrest or with exercise, or to maintain a normal cardiac output in thesetting of normal cardiac filling pressure. A left ventricular ejectionfraction of about 40% or less is indicative of congestive heart failure(by way of comparison, an ejection fraction of about 60% percent isnormal). Patients in congestive heart failure display well-knownclinical symptoms and signs, such as tachypnea, pleural effusions,fatigue at rest or with exercise, contractile dysfunction, and edema.Congestive heart failure is readily diagnosed by well known methods(see, e.g., “Consensus recommendations for the management of chronicheart failure.” Am. J. Cardiol., 83(2A):1A-38-A, 1999).

Relative severity and disease progression are assessed using well knownmethods, such as physical examination, echocardiography, radionuclideimaging, invasive hemodynamic monitoring, magnetic resonanceangiography, and exercise treadmill testing coupled with oxygen uptakestudies.

The term “ischemic heart disease” refers to any disorder resulting froman imbalance between the myocardial need for oxygen and the adequacy ofthe oxygen supply. Most cases of ischemic heart disease result fromnarrowing of the coronary arteries, as occurs in atherosclerosis orother vascular disorders.

The term “myocardial infarction” refers to a process by which ischemicdisease results in a region of the myocardium being replaced by scartissue.

The term “cardiotoxic compound” refers a compound that decreases heartfunction by directing or indirectly impairing or killing cardiomyocytes.

The term “hypertension” refers blood pressure that is considered by amedical professional (e.g., a physician or a nurse) to be higher thannormal and to carry an increased risk for developing congestive heartfailure.

The term “at risk for congestive heart failure” refers to an individualwho smokes, is obese (i.e., 20% or more over their ideal weight), hasbeen or will be exposed to a cardiotoxic compound (such as ananthracycline antibiotic), or has (or had) high blood pressure, ischemicheart disease, a myocardial infarct, a genetic defect known to increasethe risk of heart failure, a family history of heart failure, myocardialhypertrophy, hypertrophic cardiomyopathy, left ventricular systolicdysfunction, coronary bypass surgery, vascular disease, atherosclerosis,alcoholism, periocarditis, a viral infection, gingivitis, or an eatingdisorder (e.g., anorexia nervosa or bulimia), or is an alcoholic orcocaine addict.

The term “inhibits myocardial apoptosis” is meant that the treatmentinhibits death of cardiomyocytes by at least 10%, by at least 15%, by atleast 25%, by at least 50%, by at least 75%, or by at least 90%,compared to untreated cardiomyocytes.

Embodiments described herein relate to compositions and methods fortreating preventing, minimizing, and/or reversing congestive heartfailure, cardiomyopathy, and/or reduction of cardiac ejection fraction.The methods can include administering to a subject having or at risk ofcongestive heart failure, cardiomyopathy, and/or reduction of cardiacejection fraction, a therapeutically effective or prophylactic amount ofan inhibitor of 15-PGDH activity. The therapeutically effective orprophylactic amount of the 15-PGDH inhibitor can be an amount effectiveto prevent, minimize, and/or reverse congestive heart failure,cardiomyopathy, and/or reduction of cardiac ejection fraction as well asinhibit myocardial apoptosis.

In some embodiments, the congestive heart failure, cardiomyopathy,and/or reduction of cardiac ejection fraction can result from underlyingfactors, such as hypertension, ischemic heart disease, cardiotoxicity(e.g., cocaine, alcohol, an anti-ErbB2 antibody or anti-HER2 antibody,such as trastuzumab, pertuzumab, or lapatinib, or an anthracyclineantibiotic, such as doxorubicin or daunomycin), myocarditis, thyroiddisease, viral infection, gingivitis, drug abuse; alcohol abuse,periocarditis, atherosclerosis, vascular disease, hypertrophiccardiomyopathy, acute myocardial infarction or previous myocardialinfarction, left ventricular systolic dysfunction, coronary bypasssurgery, starvation, an eating disorder, or a genetic defect.

Other embodiments described herein relate to methods of preventing orreducing the risk of any type of acute or delayed cardiotoxic eventsthat are common to subjects or patients treated with chemotherapeuticagents. The method can include administering to a subject treated with achemotherapeutic agent a therapeutically effective amount of a 15-PGDHinhibitor. The cardiotoxic event that is prevented or reduced caninclude, for example, myocarditis, and cardiomyopathy, which isindicated by a reduction in left ventricular ejection fraction (LVEF),and signs and symptoms of congestive heart failure (e.g., tachycardia,dyspnea, pulmonary edema, dependent edema, cardiomegaly, hepatomegaly,oliguria, ascites, pleural effusion, and arrhythmias).

Chemotherapeutic agents that may cause cardiotoxic events may include,but are not limited to, alkylating agents, antimetabolites, anti-tumorantibiotics (e.g., anthracyclines), topoisomerase inhibitors, mitoticinhibitors hormone therapy, targeted therapeutics andimmunotherapeutics. In certain embodiments, anthracyclines may beresponsible for causing cardiomyopathy and other cardiotoxic events whenadministered as a cancer therapy, and may be optimally administeredalone or in combination with one or more additional chemotherapeuticagents according to the embodiments described herein.

A strong dose-dependent association between anthracyclines andcardiomyopathy limits the therapeutic potential of this effective classof therapeutic agents. Administration of a 15-PGDH inhibitor incombination with anthracycline can prevent or reduce the risk of anytype of acute or delayed cardiotoxic events associated withanthracycline exposure allowing the treatment to be tailored to maximizethe efficacy of these drugs.

Examples of anthracyclines that may be administered according to theembodiments described herein include, but are not limited to,doxorubicin, epirubicin, daunorubicin, idarubicin, valrubicin,pirarubicin, amrubicin, aclarubicin, zorubicin, either administered as asingle agent or in combination with other agents. Examples of additionalchemotherapeutic agents that can be administered to the subject before,during, or after anthracycline administration include an anti-ErB2 oranti-HER2 antibody, such as trastuzumab, pertuzumab, or lapatinib.

Cancer patients are typically administered a maximum safe dosage of aparticular cancer treatment or combination treatment, includingchemotherapeutics and targeted cancer therapies. A “maximum safedosage,” “maximum tolerated dosage” or “maximum recommended therapeuticdosage” is the highest amount of a therapeutic agent that can be giventhat minimizes complications or side effects to a patient whilemaintaining its efficacy as a treatment. Such a dose can be adjusted toconsider the patient's overall heath and any extenuating factors thatcould hamper the patient's recovery. Due to the severity and potentiallethal outcome of the cancer being treated, a maximum safe dosagetolerated in cancer treatment may be an amount that causes considerableand severe side effects, including cardiotoxic effects.

In some embodiments, the maximum safe dosage is represented by acumulative dose of the therapeutic agent, which is the total amount ofthe therapeutic agent given to a patient over the course of treatment.For example, anthracyclines such as doxorubicin are typicallyadministered at a dosage of 60-75 mg/m² every three to four weeks whenadministered as a single agent and 25-60 mg/m² every three to four weekswhen administered in combination with one or more additionalchemotherapeutic agents. However, according to the package insert fordoxorubicin hydrochloride injection (Teva Parenteral Medicines, Inc.),the risk of developing cardiotoxicity that manifests as potentiallyfatal congestive heart failure (CHF) increases rapidly with increasingtotal cumulative doses of doxorubicin in excess of 400 mg/m².

The 15-PGDH inhibitors described herein when administered to subject incombination with a chemotherapeutic agent can prevent or reduce the riskof cardiomyopathy arising in cancer patients receiving a maximum safedosage or maximum tolerable dosage as well as increase or extend themaximum safe dosage or maximum tolerable dosage that cancer patients canreceive. This allows cancer patients to continue to receive effectivechemotherapeutic agents when the total chemotherapeutic agent dosereaches the current cardiotoxicity based dose limit.

In some embodiments, the 15-PGDH inhibitor can be administered before,during, or after exposure to a cardiotoxic compound. In yet otherembodiments, the 15-PGDH inhibitor can be administered during two, orall three, of these periods.

In still other embodiments, the 15-PGDH inhibitor can be administeredeither prior to or after the diagnosis of congestive heart failure inthe mammal.

The methods described herein may be used to prevent cardiotoxicityduring the treatment of any type of cancer including, but not limitedto, bone cancer, bladder cancer, brain cancer, neuroblastoma, breastcancer, cancer of the urinary tract, carcinoma, cervical cancer,childhood cancers (e.g., astrocytoma, brain stem glioma, NCS atypicalteratoid/rhabdoid tumor, CNS embryonal tumor, CNS Germ Cell tumors,craniopharyngioma, ependymoma, kidney tumors, acute lymphoblasticleukemia, acute myeloid leukemia, and other types of leukemia; Hodgkinlymphoma, non-Hodgkin lymphoma, Ewing sarcoma, osteosarcoma andmalignant fibrous histiocytoma of the bone, rhabdomyosarcoma, softtissue sarcoma, and Wilms' tumor,), colon cancer, esophageal cancer,gastric cancer, head and neck cancer, hepatocellular cancer, livercancer, lung cancer, lymphoma and leukemia, melanoma, ovarian cancer,pancreatic cancer, pituitary cancer, prostate cancer, rectal cancer,renal cancer, sarcoma, stomach cancer, testicular cancer, thyroidcancer, and uterine cancer.

In some embodiments, a therapeutically effective amount of the 15-PGDHinhibitor administered to a subject in need thereof can be an amounteffective to increase or improve left ventrical ejection fraction, leftventricular end systolic volume, wall motion score index, and/or sixminute walk distance at least about 30 meters by at least about 2%, atleast about 3%, at least about 4%, at least about 5%, at least about 6%,at least about 7%, at least about 8%, at least about 9%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, or at leastabout 50%.

In other embodiments, a therapeutically effective amount of the 15-PGDHinhibitor administered to a subject in need thereof can be amounteffective to mitigate decreases in left ventrical ejection fraction,left ventricular end systolic volume, wall motion score index, and/orsix minute walk distance at least about 30 meters caused by cardiotoxiccompounds by at least about 2%, at least about 3%, at least about 4%, atleast about 5%, at least about 6%, at least about 7%, at least about 8%,at least about 9%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, or at least about 50%.

15-PGDH inhibitors can be identified using assays in which putativeinhibitor compounds are applied to cells expressing 15-PGDH and then thefunctional effects on 15-PGDH activity are determined. Samples or assayscomprising 15-PGDH that are treated with a potential inhibitor arecompared to control samples without the inhibitor to examine the extentof effect. Control samples (untreated with modulators) are assigned arelative 15-PGDH activity value of 100%. Inhibition of 15-PGDH isachieved when the 15-PGDH activity value relative to the control isabout 80%, optionally 50% or 25%, 10%, 5% or 1%.

Agents tested as inhibitors of SCD (e.g., 15-PGDH) can be any smallchemical molecule or compound. Typically, test compounds will be smallchemical molecules, natural products, or peptides. The assays aredesigned to screen large chemical libraries by automating the assaysteps and providing compounds from any convenient source to assays,which are typically run in parallel (e.g., in microtiter formats onmicrotiter plates in robotic assays).

In some embodiments, the 15-PGDH inhibitor can include a compound havingthe following formula (I):

-   -   wherein n is 0-2;    -   Y¹, Y², and R¹ are the same or different and are each selected        from the group consisting of hydrogen, substituted or        unsubstituted C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl,        C₃-C₂₀ aryl, heteroaryl, heterocycloalkenyl containing from 5-6        ring atoms (wherein from 1-3 of the ring atoms is independently        selected from N, NH, N(C₁-C₆ alkyl), NC(O) (C₁-C₆ alkyl), O, and        S), C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, halo, —Si(C₁-C₃ alkyl)₃,        hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄        alkynyloxy, C₅-C₂₀ aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl        (—CO-alkyl) and C₆-C₂₀ arylcarbonyl (—CO-aryl)), acyloxy        (—O-acyl), C₂-C₂₄ alkoxycarbonyl (—(CO)—O-alkyl), C₆-C₂₀        aryloxycarbonyl (—(CO)—O-aryl), C₂-C₂₄ alkylcarbonato        (—O—(CO)—O-alkyl), C₆-C₂₀ arylcarbonato (—O—(CO)—O-aryl),        carboxy (—COOH), carboxylato (—COO⁻), carbamoyl (—(CO)—NH₂),        C₁-C₂₄ alkyl-carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), arylcarbamoyl        (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH₂), carbamido        (—NH—(CO)—NH₂), cyano(—CN), isocyano (—N⁺C⁻), cyanato (—O—CN),        isocyanato (—O—N⁺═C⁻), isothiocyanato (—S—CN), azido (—N═N⁺═N⁻),        formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH₂), C₁-C₂₄        alkyl amino, C₅-C₂₀ aryl amino, C₂-C₂₄ alkylamido        (—NH—(CO)-alkyl), C₆-C₂₀ arylamido (—NH—(CO)-aryl), imino        (—CR═NH where R is hydrogen, C₁-C₂₄ alkyl, C₅-C₂₀ aryl, C₆-C₂₄        alkaryl, C₆-C₂₄ aralkyl, etc.), alkylimino (—CR═N(alkyl), where        R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino        (—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.),        nitro (—NO₂), nitroso (—NO), sulfo (—SO₂—OH), sulfonato        (—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl; also termed        “alkylthio”), arylsulfanyl (—S-aryl; also termed “arylthio”),        C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl        (—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀        arylsulfonyl (—SO₂-aryl), sulfonamide (—SO₂—NH2, —SO₂NY₂        (wherein Y is independently H, aryl or alkyl), phosphono        (—P(O)(OH)₂), phosphonato (—P(O)(O⁻)₂), phosphinato (—P(O)(O⁻)),        phospho (—PO₂), phosphino (—PH₂), polyalkylethers, phosphates,        phosphate esters, groups incorporating amino acids or other        moieties expected to bear positive or negative charge at        physiological pH, combinations thereof, and wherein Y¹ and Y²        may be linked to form a cyclic or polycyclic ring, wherein the        ring is a substituted or unsubstituted aryl, a substituted or        unsubstituted heteroaryl, a substituted or unsubstituted        cycloalkyl, and a substituted or unsubstituted heterocyclyl;    -   U¹ is N, C—R², or C—NR³R⁴, wherein R² is selected from the group        consisting of a H, a lower alkyl group, O, (CH₂)_(n1)OR′        (wherein n1=1, 2, or 3), CF₃, CH₂—CH₂X, O—CH₂—CH₂X,        CH₂—CH₂—CH₂X, O—CH₂—CH₂X, X, (wherein X=H, F, Cl, Br, or I), CN,        (C═O)—R′, (C═O)N(R′)₂, O(CO)R′, COOR′ (wherein R′ is H or a        lower alkyl group), and wherein R¹ and R² may be linked to form        a cyclic or polycyclic ring, wherein R³ and R⁴ are the same or        different and are each selected from the group consisting of H,        a lower alkyl group, O, (CH₂)_(n1)OR′ (wherein n1=1, 2, or 3),        CF₃, CH₂—CH₂X, CH₂—CH₂—CH₂X, (wherein X=H, F, Cl, Br, or I), CN,        (C═O)—R′, (C═O)N(R′)₂, COOR′ (wherein R′ is H or a lower alkyl        group), and R³ or R⁴ may be absent;    -   X¹ and X² are independently N or C, and wherein when X¹ and/or        X² are N, Y¹ and/or Y², respectively, are absent;    -   Z¹ is O, S, CR^(a)R^(b) or NR^(a), wherein R^(a) and R^(b) are        independently H or a C₁₋₈ alkyl, which is linear, branched, or        cyclic, and which is unsubstituted or substituted;    -   and pharmaceutically acceptable salts thereof.

Examples of 15-PGDH inhibitors having formulas (I) include the followingcompounds:

and pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PGDH inhibitor can include a compoundhaving the following formula (II):

-   -   wherein n is 0-2    -   X⁴, X⁵, X⁶, and X⁷ are independently N or CR^(c);    -   R¹, R⁶, R⁷, and R^(c) are independently selected from the group        consisting of hydrogen, substituted or unsubstituted C₁-C₂₄        alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₃-C₂₀ aryl, heteroaryl,        heterocycloalkenyl containing from 5-6 ring atoms (wherein from        1-3 of the ring atoms is independently selected from N, NH,        N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S), C₆-C₂₄ alkaryl,        C₆-C₂₄ aralkyl, halo, —Si(C₁-C₃ alkyl)₃, hydroxyl, sulfhydryl,        C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₀        aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl (—CO-alkyl) and        C₆-C₂₀ arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl), C₂-C₂₄        alkoxycarbonyl (—(CO)—O-alkyl), C₆-C₂₀ aryloxycarbonyl        (—(CO)—O-aryl), C₂-C₂₄ alkylcarbonato (—O—(CO)—O-alkyl), C₆-C₂₀        arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato        (—COO⁻), carbamoyl (—(CO)—NH₂), C₁-C₂₄ alkyl-carbamoyl        (—(CO)—NH(C₁-C₂₄ alkyl)), arylcarbamoyl (—(CO)—NH-aryl),        thiocarbamoyl (—(CS)—NH₂), carbamido (—NH—(CO)—NH₂), cyano(—CN),        isocyano (—N⁺C⁻), cyanato (—O—CN), isocyanato (—O—N⁺═C⁻),        isothiocyanato (—S—CN), azido (—N═N⁺═N⁻), formyl (—(CO)—H),        thioformyl (—(CS)—H), amino (—NH₂), C₁-C₂₄ alkyl amino, C₅-C₂₀        aryl amino, C₂-C₂₄ alkylamido (—NH—(CO)-alkyl), C₆-C₂₀ arylamido        (—NH—(CO)-aryl), imino (—CR═NH where R is hydrogen, C₁-C₂₄        alkyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.),        alkylimino (—CR═N(alkyl), where R=hydrogen, alkyl, aryl,        alkaryl, aralkyl, etc.), arylimino (—CR═N(aryl), where        R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO₂), nitroso        (—NO), sulfo (—SO₂—OH), sulfonato (—SO₂—O⁻), C₁-C₂₄        alkylsulfanyl (—S-alkyl; also termed “alkylthio”), arylsulfanyl        (—S-aryl; also termed “arylthio”), C₁-C₂₄ alkylsulfinyl        (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl (—(SO)-aryl), C₁-C₂₄        alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀ arylsulfonyl (—SO₂-aryl),        sulfonamide (—SO₂—NH2, —SO₂NY₂ (wherein Y is independently H,        aryl or alkyl), phosphono (—P(O)(OH)₂), phosphonato        (—P(O)(O⁻)₂), phosphinato (—P(O)(O⁻)), phospho (—PO₂), phosphino        (—PH₂), polyalkylethers, phosphates, phosphate esters, groups        incorporating amino acids or other moieties expected to bear        positive or negative charge at physiological pH, combinations        thereof, and wherein R⁶ and R⁷ may be linked to form a cyclic or        polycyclic ring, wherein the ring is a substituted or        unsubstituted aryl, a substituted or unsubstituted heteroaryl, a        substituted or unsubstituted cycloalkyl, and a substituted or        unsubstituted heterocyclyl;    -   U¹ is N, C—R², or C—NR³R⁴, wherein R² is selected from the group        consisting of a H, a lower alkyl group, O, (CH₂)_(n1)OR′        (wherein n1=1, 2, or 3), CF₃, CH₂—CH₂X, O—CH₂—CH₂X,        CH₂—CH₂—CH₂X, O—CH₂—CH₂X, X, (wherein X=H, F, Cl, Br, or I), CN,        (C═O)—R′, (C═O)N(R′)₂, O(CO)R′, COOR′ (wherein R′ is H or a        lower alkyl group), and wherein R¹ and R² may be linked to form        a cyclic or polycyclic ring, wherein R³ and R⁴ are the same or        different and are each selected from the group consisting of H,        a lower alkyl group, O, (CH₂)_(n1)OR′ (wherein n1=1, 2, or 3),        CF₃, CH₂—CH₂X, CH₂—CH₂—CH₂X, (wherein X=H, F, Cl, Br, or I), CN,        (C═O)—R′, (C═O)N(R′)₂, COOR′ (wherein R′ is H or a lower alkyl        group), and R³ or R⁴ may be absent;    -   Z¹ is O, S, CR^(a)R^(b) or NR^(a), wherein R^(a) and R^(b) are        independently H or a C₁₋₈ alkyl, which is linear, branched, or        cyclic, and which is unsubstituted or substituted;    -   and pharmaceutically acceptable salts thereof.

Examples of 15-PGDH inhibitors having formulas (II) include thefollowing compounds:

and pharmaceutically acceptable salts thereof.

In yet other embodiments, the 15-PGDH inhibitor can include a compoundhaving the following formula (III) or (IV):

-   -   wherein n is 0-2    -   X⁶ is independently is N or CR^(c);    -   R¹, R⁶, R⁷, and R^(c) are independently selected from the group        consisting of hydrogen, substituted or unsubstituted C₁-C₂₄        alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₃-C₂₀ aryl, heteroaryl,        heterocycloalkenyl containing from 5-6 ring atoms (wherein from        1-3 of the ring atoms is independently selected from N, NH,        N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S), C₆-C₂₄ alkaryl,        C₆-C₂₄ aralkyl, halo, —Si(C₁-C₃ alkyl)₃, hydroxyl, sulfhydryl,        C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₀        aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl (—CO-alkyl) and        C₆-C₂₀ arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl), C₂-C₂₄        alkoxycarbonyl (—(CO)—O-alkyl), C₆-C₂₀ aryloxycarbonyl        (—(CO)—O-aryl), C₂-C₂₄ alkylcarbonato (—O—(CO)—O-alkyl), C₆-C₂₀        arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato        (—COO⁻), carbamoyl (—(CO)—NH₂), C₁-C₂₄ alkyl-carbamoyl        (—(CO)—NH(C₁-C₂₄ alkyl)), arylcarbamoyl (—(CO)—NH-aryl),        thiocarbamoyl (—(CS)—NH₂), carbamido (—NH—(CO)—NH₂), cyano(—CN),        isocyano (—N⁺C⁻), cyanato (—O—CN), isocyanato (—O—N⁺═C⁻),        isothiocyanato (—S—CN), azido (—N═N⁺═N⁻), formyl (—(CO)—H),        thioformyl (—(CS)—H), amino (—NH₂), C₁-C₂₄ alkyl amino, C₅-C₂₀        aryl amino, C₂-C₂₄ alkylamido (—NH—(CO)-alkyl), C₆-C₂₀ arylamido        (—NH—(CO)-aryl), imino (—CR═NH where R is hydrogen, C₁-C₂₄        alkyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.),        alkylimino (—CR═N(alkyl), where R=hydrogen, alkyl, aryl,        alkaryl, aralkyl, etc.), arylimino (—CR═N(aryl), where        R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO₂), nitroso        (—NO), sulfo (—SO₂—OH), sulfonato (—SO₂—O⁻), C₁-C₂₄        alkylsulfanyl (—S-alkyl; also termed “alkylthio”), arylsulfanyl        (—S-aryl; also termed “arylthio”), C₁-C₂₄ alkylsulfinyl        (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl (—(SO)-aryl), C₁-C₂₄        alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀ arylsulfonyl (—SO₂-aryl),        sulfonamide (—SO₂—NH2, —SO₂NY₂ (wherein Y is independently H,        aryl or alkyl), phosphono (—P(O)(OH)₂), phosphonato        (—P(O)(O⁻)₂), phosphinato (—P(O)(O⁻)), phospho (—PO₂), phosphino        (—PH₂), polyalkylethers, phosphates, phosphate esters, groups        incorporating amino acids or other moieties expected to bear        positive or negative charge at physiological pH, combinations        thereof, and wherein R⁶ and R⁷ may be linked to form a cyclic or        polycyclic ring, wherein the ring is a substituted or        unsubstituted aryl, a substituted or unsubstituted heteroaryl, a        substituted or unsubstituted cycloalkyl, and a substituted or        unsubstituted heterocyclyl;    -   U¹ is N, C—R², or C—NR³R⁴, wherein R² is selected from the group        consisting of a H, a lower alkyl group, O, (CH₂)_(n1)OR′        (wherein n1=1, 2, or 3), CF₃, CH₂—CH₂X, O—CH₂—CH₂X,        CH₂—CH₂—CH₂X, O—CH₂—CH₂X, X, (wherein X=H, F, Cl, Br, or I), CN,        (C═O)—R′, (C═O)N(R′)₂, O(CO)R′, COOR′ (wherein R′ is H or a        lower alkyl group), and wherein R¹ and R² may be linked to form        a cyclic or polycyclic ring, wherein R³ and R⁴ are the same or        different and are each selected from the group consisting of H,        a lower alkyl group, O, (CH₂)_(n1)OR′ (wherein n1=1, 2, or 3),        CF₃, CH₂—CH₂X, CH₂—CH₂—CH₂X, (wherein X=H, F, Cl, Br, or I), CN,        (C═O)—R′, (C═O)N(R′)₂, COOR′ (wherein R′ is H or a lower alkyl        group), and R³ or R⁴ may be absent;    -   Z¹ is O, S, CR^(a)R^(b) or NR^(a), wherein R^(a) and R^(b) are        independently H or a C₁₋₈ alkyl, which is linear, branched, or        cyclic, and which is unsubstituted or substituted;    -   and pharmaceutically acceptable salts thereof.

In some embodiments, R¹ is selected from the group consisting ofbranched or linear alkyl including —(CH₂)n₁CH₃ (n₁=0-7),

wherein n₂=0-6 and X is any of the following: CF_(y)H_(z) (y+z=3),CCl_(y)H_(z) (y+z=3), OH, OAc, OMe, R⁷¹, OR⁷², CN, N(R⁷³)₂,

(n₃=0-5, m=1-5), and

(n₄=0-5).

In other embodiments, R⁶ and R⁷ can each independently be one of thefollowing:

each R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵,R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹,R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³,R⁶⁴, R⁶⁵, R⁶⁶, R⁶⁷, R⁶⁸, R⁶⁹, R⁷⁰, R⁷¹, R⁷², R⁷³, and R⁷⁴, are the sameor different and are independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl,C₂-C₂₄ alkynyl, C₃-C₂₀ aryl, heterocycloalkenyl containing from 5-6 ringatoms, (wherein from 1-3 of the ring atoms is independently selectedfrom N, NH, N(C₁-C₆ alkyl), NC(O) (C₁-C₆ alkyl), O, and S), heteroarylor heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 ofthe ring atoms is independently selected from N, NH, N(C₁-C₃ alkyl), O,and S), C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, halo, silyl, hydroxyl,sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₀aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl (—CO-alkyl) and C₆-C₂₀arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl), C₂-C₂₄ alkoxycarbonyl(—(CO)—O-alkyl), C₆-C₂₀ aryloxycarbonyl (—(CO)—O-aryl), C₂-C₂₄alkylcarbonato (—O—(CO)—O-alkyl), C₆-C₂₀ arylcarbonato (—O—(CO)—O-aryl),carboxy (—COOH), carboxylato (—COO⁻), carbamoyl (—(CO)—NH₂), C₁-C₂₄alkyl-carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), arylcarbamoyl (—(CO)—NH-aryl),thiocarbamoyl (—(CS)—NH₂), carbamido (—NH—(CO)—NH₂), cyano(—CN),isocyano (—N⁺C⁻), cyanato (—O—CN), isocyanato (—O—N⁺═C⁻), isothiocyanato(—S—CN), azido (—N═N⁺═N⁻), formyl (—(CO)—H), thioformyl (—(CS)—H), amino(—NH₂), C₁-C₂₄ alkyl amino, C₅-C₂₀ aryl amino, C₂-C₂₄ alkylamido(—NH—(CO)-alkyl), C₆-C₂₀ arylamido (—NH—(CO)-aryl), sulfanamido(—SO₂N(R)₂ where R is independently H, alkyl, aryl or heteroaryl), imino(—CR═NH where R is hydrogen, C₁-C₂₄ alkyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl,C₆-C₂₄ aralkyl, etc.), alkylimino (—CR═N(alkyl), where R=hydrogen,alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR═N(aryl), whereR=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO₂), nitroso (—NO),sulfo (—SO₂—OH), sulfonato (—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl;also termed “alkylthio”), arylsulfanyl (—S-aryl; also termed“arylthio”), C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl(—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀ arylsulfonyl(—SO₂-aryl), sulfonamide (—SO₂—NH₂, —SO₂NY₂ (wherein Y is independentlyH, aryl or alkyl), phosphono (—P(O)(OH)₂), phosphonato (—P(O)(O⁻)₂),phosphinato (—P(O)(O⁻)), phospho (—PO₂), phosphino (—PH₂), polyalkylethers (—[(CH₂)_(n)O]_(m)), phosphates, phosphate esters [—OP(O)(OR)₂where R=H, methyl or other alkyl], groups incorporating amino acids orother moieties expected to bear positive or negative charge atphysiological pH, and combinations thereof, and pharmaceuticallyacceptable salts thereof.

In still other embodiments, R⁶ and R⁷ can independently be a group thatimproves aqueous solubility, for example, a phosphate ester (—OPO₃H₂), aphenyl ring linked to a phosphate ester (—OPO₃H₂), a phenyl ringsubstituted with one or more methoxyethoxy groups, or a morpholine, oran aryl or heteroaryl ring substituted with such a group.

Examples of 15-PGDH inhibitors having formulas (III) or (IV) include thefollowing compounds:

and pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PGDH inhibitor can include a compoundhaving the following formula (V):

-   -   wherein n is 0-2    -   X⁶ is independently is N or CR^(c)    -   R¹, R⁶, R⁷, and R^(c) are each independently selected from the        group consisting of hydrogen, substituted or unsubstituted        C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₃-C₂₀ aryl,        heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms        (wherein from 1-3 of the ring atoms is independently selected        from N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S),        C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, halo, —Si(C₁-C₃ alkyl)₃,        hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄        alkynyloxy, C₅-C₂₀ aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl        (—CO-alkyl) and C₆-C₂₀ arylcarbonyl (—CO-aryl)), acyloxy        (—O-acyl), C₂-C₂₄ alkoxycarbonyl (—(CO)—O-alkyl), C₆-C₂₀        aryloxycarbonyl (—(CO)—O-aryl), C₂-C₂₄ alkylcarbonato        (—O—(CO)—O-alkyl), C₆-C₂₀ arylcarbonato (—O—(CO)—O-aryl),        carboxy (—COOH), carboxylato (—COO⁻), carbamoyl (—(CO)—NH₂),        C₁-C₂₄ alkyl-carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), arylcarbamoyl        (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH₂), carbamido        (—NH—(CO)—NH₂), cyano(—CN), isocyano (—N⁺C⁻), cyanato (—O—CN),        isocyanato (—O—N⁺═C⁻), isothiocyanato (—S—CN), azido (—N═N⁺═N⁻),        formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH₂), C₁-C₂₄        alkyl amino, C₅-C₂₀ aryl amino, C₂-C₂₄ alkylamido        (—NH—(CO)-alkyl), C₆-C₂₀ arylamido (—NH—(CO)-aryl), imino        (—CR═NH where R is hydrogen, C₁-C₂₄ alkyl, C₅-C₂₀ aryl, C₆-C₂₄        alkaryl, C₆-C₂₄ aralkyl, etc.), alkylimino (—CR═N(alkyl), where        R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino        (—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.),        nitro (—NO₂), nitroso (—NO), sulfo (—SO₂—OH), sulfonato        (—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl; also termed        “alkylthio”), arylsulfanyl (—S-aryl; also termed “arylthio”),        C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl        (—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀        arylsulfonyl (—SO₂-aryl), sulfonamide (—SO₂—NH2, —SO₂NY₂        (wherein Y is independently H, aryl or alkyl), phosphono        (—P(O)(OH)₂), phosphonato (—P(O)(O⁻)₂), phosphinato (—P(O)(O⁻)),        phospho (—PO₂), phosphino (—PH₂), polyalkylethers, phosphates,        phosphate esters, groups incorporating amino acids or other        moieties expected to bear positive or negative charge at        physiological pH, combinations thereof, and wherein R⁶ and R⁷        may be linked to form a cyclic or polycyclic ring, wherein the        ring is a substituted or unsubstituted aryl, a substituted or        unsubstituted heteroaryl, a substituted or unsubstituted        cycloalkyl, and a substituted or unsubstituted heterocyclyl;    -   U¹ is N, C—R², or C—NR³R⁴, wherein R² is selected from the group        consisting of a H, a lower alkyl group, O, (CH₂)_(n1)OR′        (wherein n1=1, 2, or 3), CF₃, CH₂—CH₂X, O—CH₂—CH₂X,        CH₂—CH₂—CH₂X, O—CH₂—CH₂X, X, (wherein X=H, F, Cl, Br, or I), CN,        (C═O)—R′, (C═O)N(R′)₂, O(CO)R′, COOR′ (wherein R′ is H or a        lower alkyl group), and wherein R¹ and R² may be linked to form        a cyclic or polycyclic ring, wherein R³ and R⁴ are the same or        different and are each selected from the group consisting of H,        a lower alkyl group, O, (CH₂)_(n1)OR′ (wherein n1=1, 2, or 3),        CF₃, CH₂—CH₂X, CH₂—CH₂—CH₂X, (wherein X=H, F, Cl, Br, or I), CN,        (C═O)—R′, (C═O)N(R′)₂, COOR′ (wherein R′ is H or a lower alkyl        group), and R³ or R⁴ may be absent;    -   and pharmaceutically acceptable salts thereof.

In some embodiments, R¹ is selected from the group consisting ofbranched or linear alkyl including —(CH₂)n₁CH₃ (n₁=0-7),

wherein n₂=0-6 and X is any of the following: CF_(y)H_(z) (y+z=3),CCl_(y)H_(z) (y+z=3), OH, OAc, OMe, R⁷¹, OR⁷², CN, N(R⁷³)₂,

(n₃=0-5, m=1-5), and

(n₄=0-5).

In other embodiments, R⁶ and R⁷ can each independently be one of thefollowing:

each R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵,R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹,R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³,R⁶⁴, R⁶⁵, R⁶⁶, R⁶⁷, R⁶⁸, R⁶⁹, R⁷⁰, R⁷¹, R⁷², R⁷³, and R⁷⁴, are the sameor different and are independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl,C₂-C₂₄ alkynyl, C₃-C₂₀ aryl, heterocycloalkenyl containing from 5-6 ringatoms, (wherein from 1-3 of the ring atoms is independently selectedfrom N, NH, N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S), heteroaryl orheterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of thering atoms is independently selected from N, NH, N(C₁-C₃ alkyl), O, andS), C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, halo, silyl, hydroxyl, sulfhydryl,C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₀ aryloxy,acyl (including C₂-C₂₄ alkylcarbonyl (—CO-alkyl) and C₆-C₂₀ arylcarbonyl(—CO-aryl)), acyloxy (—O-acyl), C₂-C₂₄ alkoxycarbonyl (—(CO)—O-alkyl),C₆-C₂₀ aryloxycarbonyl (—(CO)—O-aryl), C₂-C₂₄ alkylcarbonato(—O—(CO)—O-alkyl), C₆-C₂₀ arylcarbonato (—O—(CO)—O-aryl), carboxy(—COOH), carboxylato (—COO⁻), carbamoyl (—(CO)—NH₂), C₁-C₂₄alkyl-carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), arylcarbamoyl (—(CO)—NH-aryl),thiocarbamoyl (—(CS)—NH₂), carbamido (—NH—(CO)—NH₂), cyano(—CN),isocyano (—N⁺C⁻), cyanato (—O—CN), isocyanato (—O—N⁺═C⁻), isothiocyanato(—S—CN), azido (—N═N⁺═N⁻), formyl (—(CO)—H), thioformyl (—(CS)—H), amino(—NH₂), C₁-C₂₄ alkyl amino, C₅-C₂₀ aryl amino, C₂-C₂₄ alkylamido(—NH—(CO)-alkyl), C₆-C₂₀ arylamido (—NH—(CO)-aryl), sulfanamido(—SO₂N(R)₂ where R is independently H, alkyl, aryl or heteroaryl), imino(—CR═NH where R is hydrogen, C₁-C₂₄ alkyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl,C₆-C₂₄ aralkyl, etc.), alkylimino (—CR═N(alkyl), where R=hydrogen,alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (—CR═N(aryl), whereR=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (—NO₂), nitroso (—NO),sulfo (—SO₂—OH), sulfonato (—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl;also termed “alkylthio”), arylsulfanyl (—S-aryl; also termed“arylthio”), C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl(—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀ arylsulfonyl(—SO₂-aryl), sulfonamide (—SO₂—NH₂, —SO₂NY₂ (wherein Y is independentlyH, aryl or alkyl), phosphono (—P(O)(OH)₂), phosphonato (—P(O)(O⁻)₂),phosphinato (—P(O)(O⁻)), phospho (—PO₂), phosphino (—PH₂), polyalkylethers (—[(CH₂)_(n)O]_(m)), phosphates, phosphate esters [—OP(O)(OR)₂where R=H, methyl or other alkyl], groups incorporating amino acids orother moieties expected to bear positive or negative charge atphysiological pH, and combinations thereof, and pharmaceuticallyacceptable salts thereof.

In still other embodiments, R⁶ and R⁷ can independently be a group thatimproves aqueous solubility, for example, a phosphate ester (—OPO₃H₂), aphenyl ring linked to a phosphate ester (—OPO₃H₂), a phenyl ringsubstituted with one or more methoxyethoxy groups, or a morpholine, oran aryl or heteroaryl ring substituted with such a group.

In other embodiments, the 15-PGDH inhibitor can include a compoundhaving the following formula (VI):

-   -   wherein n=0-2;    -   X⁶ is N or CR^(c);    -   R¹ is selected from the group consisting of branched or linear        alkyl including —(CH₂)n₁CH₃ (n₁=0-7),

wherein n₂=0-6 and X is any of the following: CF_(y)H_(z) (y+z=3),CCl_(y)H_(z) (y+z=3), OH, OAc, OMe, R⁷¹, OR⁷², CN, N(R⁷³)₂,

(n₃=0-5, m=1-5), and

(n₄=0-5).

-   -   R⁵ is selected from the group consisting of H, Cl, F, NH₂, and        N(R⁷⁶)₂;    -   R⁶ and R⁷ can each independently be one of the following:

each R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵,R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹,R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³,R⁶⁴, R⁶⁵, R⁶⁶, R⁶⁷, R⁶⁸, R⁶⁹, R⁷⁰, R⁷¹, R⁷², R⁷³, and R⁷⁴, and R^(c) arethe same or different and are independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁-C₂₄ alkyl,C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₃-C₂₀ aryl, heterocycloalkenylcontaining from 5-6 ring atoms, (wherein from 1-3 of the ring atoms isindependently selected from N, NH, N(C₁-C₆ alkyl), NC(O) (C₁-C₆ alkyl),O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms,(wherein from 1-6 of the ring atoms is independently selected from N,NH, N(C₁-C₃ alkyl), O, and S), C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, halo,silyl, hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄alkynyloxy, C₅-C₂₀ aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl(—CO-alkyl) and C₆-C₂₀ arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl),C₂-C₂₄ alkoxycarbonyl (—(CO)—O-alkyl), C₆-C₂₀ aryloxycarbonyl(—(CO)—O-aryl), C₂-C₂₄ alkylcarbonato (—O—(CO)—O-alkyl), C₆-C₂₀arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (—COO⁻),carbamoyl (—(CO)—NH₂), C₁-C₂₄ alkyl-carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)),arylcarbamoyl (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH₂), carbamido(—NH—(CO)—NH₂), cyano(—CN), isocyano (—N⁺C⁻), cyanato (—O—CN),isocyanato (—O—N⁺═C⁻), isothiocyanato (—S—CN), azido (—N═N⁺═N⁻), formyl(—(CO)—H), thioformyl (—(CS)—H), amino (—NH₂), C₁-C₂₄ alkyl amino,C₅-C₂₀ aryl amino, C₂-C₂₄ alkylamido (—NH—(CO)-alkyl), C₆-C₂₀ arylamido(—NH—(CO)-aryl), sulfanamido (—SO₂N(R)₂ where R is independently H,alkyl, aryl or heteroaryl), imino (—CR═NH where R is hydrogen, C₁-C₂₄alkyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.), alkylimino(—CR═N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.),arylimino (—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.),nitro (—NO₂), nitroso (—NO), sulfo (—SO₂—OH), sulfonato (—SO₂—O⁻),C₁-C₂₄ alkylsulfanyl (—S-alkyl; also termed “alkylthio”), arylsulfanyl(—S-aryl; also termed “arylthio”), C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl),C₅-C₂₀ arylsulfinyl (—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl),C₅-C₂₀ arylsulfonyl (—SO₂-aryl), sulfonamide (—SO₂—NH₂, —SO₂NY₂ (whereinY is independently H, aryl or alkyl), phosphono (—P(O)(OH)₂),phosphonato (—P(O)(O⁻)₂), phosphinato (—P(O)(O⁻)), phospho (—PO₂),phosphino (—PH₂), polyalkyl ethers (—[(CH₂)_(n)O]_(m)), phosphates,phosphate esters [—OP(O)(OR)₂ where R=H, methyl or other alkyl], groupsincorporating amino acids or other moieties expected to bear positive ornegative charge at physiological pH, and combinations thereof, andpharmaceutically acceptable salts thereof.

In other embodiments, the 15-PGDH inhibitor can include a compoundhaving the following formula (VII):

-   -   wherein n=0-2;    -   X⁶ is N or CR^(c);    -   R¹ is selected from the group consisting of branched or linear        alkyl including —(CH₂)n₁CH₃ (n₁=0-7),

wherein n₂=0-6 and X is any of the following: CF_(y)H_(z) (y+z=3),CCl_(y)H_(z) (y+z=3), OH, OAc, OMe, R⁷¹, OR⁷², CN, N(R⁷³)₂,

(n₃=0-5, m=1-5), and

(n₄=0-5).

-   -   R⁵ is selected from the group consisting of H, Cl, F, NH₂, and        N(R⁷⁶)₂;    -   R⁷ can each independently be one of the following:

each R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵,R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹,R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, R⁶², R⁶³,R⁶⁴, R⁶⁵, R⁶⁶, R⁶⁷, R⁶⁸, R⁶⁹, R⁷⁰, R⁷¹, R⁷², R⁷³, and R⁷⁴, and R^(c) arethe same or different and are independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁-C₂₄ alkyl,C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl, C₃-C₂₀ aryl, heterocycloalkenylcontaining from 5-6 ring atoms, (wherein from 1-3 of the ring atoms isindependently selected from N, NH, N(C₁-C₆ alkyl), NC(O) (C₁-C₆ alkyl),O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms,(wherein from 1-6 of the ring atoms is independently selected from N,NH, N(C₁-C₃ alkyl), O, and S), C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, halo,silyl, hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄alkynyloxy, C₅-C₂₀ aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl(—CO-alkyl) and C₆-C₂₀ arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl),C₂-C₂₄ alkoxycarbonyl (—(CO)—O-alkyl), C₆-C₂₀ aryloxycarbonyl(—(CO)—O-aryl), C₂-C₂₄ alkylcarbonato (—O—(CO)—O-alkyl), C₆-C₂₀arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (—COO⁻),carbamoyl (—(CO)—NH₂), C₁-C₂₄ alkyl-carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)),arylcarbamoyl (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH₂), carbamido(—NH—(CO)—NH₂), cyano(—CN), isocyano (—N⁺C⁻), cyanato (—O—CN),isocyanato (—O—N⁺═C⁻), isothiocyanato (—S—CN), azido (—N═N⁺═N⁻), formyl(—(CO)—H), thioformyl (—(CS)—H), amino (—NH₂), C₁-C₂₄ alkyl amino,C₅-C₂₀ aryl amino, C₂-C₂₄ alkylamido (—NH—(CO)-alkyl), C₆-C₂₀ arylamido(—NH—(CO)-aryl), sulfanamido (—SO₂N(R)₂ where R is independently H,alkyl, aryl or heteroaryl), imino (—CR═NH where R is hydrogen, C₁-C₂₄alkyl, C₅-C₂₀ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.), alkylimino(—CR═N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.),arylimino (—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.),nitro (—NO₂), nitroso (—NO), sulfo (—SO₂—OH), sulfonato (—SO₂—O⁻),C₁-C₂₄ alkylsulfanyl (—S-alkyl; also termed “alkylthio”), arylsulfanyl(—S-aryl; also termed “arylthio”), C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl),C₅-C₂₀ arylsulfinyl (—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl),C₅-C₂₀ arylsulfonyl (—SO₂-aryl), sulfonamide (—SO₂—NH₂, —SO₂NY₂ (whereinY is independently H, aryl or alkyl), phosphono (—P(O)(OH)₂),phosphonato (—P(O)(O⁻)₂), phosphinato (—P(O)(O⁻)), phospho (—PO₂),phosphino (—PH₂), polyalkyl ethers (—[(CH₂)_(n)O]_(m)), phosphates,phosphate esters [—OP(O)(OR)₂ where R=H, methyl or other alkyl], groupsincorporating amino acids or other moieties expected to bear positive ornegative charge at physiological pH, and combinations thereof, andpharmaceutically acceptable salts thereof.

Examples of compounds having formulas (V), (VI), or (VII) are selectedfrom the group consisting of:

-   -   and pharmaceutically acceptable salts thereof.

In certain embodiments, the 15-PGDH inhibitor having formula (I), (II),(III), (IV), (V), (VI), and (VII) can be selected that can ia) at 2.5 μMconcentration, stimulate a Vaco503 reporter cell line expressing a15-PGDH luciferase fusion construct to a luciferase output level ofgreater than 70 (using a scale on which a value of 100 indicates adoubling of reporter output over baseline); iia) at 2.5 μM concentrationstimulate a V9m reporter cell line expressing a 15-PGDH luciferasefusion construct to a luciferase output level of greater than 75; iiia)at 7.5 μM concentration stimulate a LS174T reporter cell line expressinga 15-PGDH luciferase fusion construct to a luciferase output level ofgreater than 70; and iva) at 7.5 μM concentration, does not activate anegative control V9m cell line expressing TK-renilla luciferase reporterto a level greater than 20; and va) inhibits the enzymatic activity ofrecombinant 15-PGDH protein at an IC₅₀ of less than 1 μM.

In other embodiments, the 15-PGDH inhibitor can ib) at 2.5 μMconcentration, stimulate a Vaco503 reporter cell line expressing a15-PGDH luciferase fusion construct to increase luciferase output; iib)at 2.5 μM concentration stimulate a V9m reporter cell line expressing a15-PGDH luciferase fusion construct to increase luciferase output; iiib)at 7.5 μM concentration stimulate a LS174T reporter cell line expressinga 15-PGDH luciferase fusion construct to increase luciferase output;ivb) at 7.5 μM concentration, does not activate a negative control V9mcell line expressing TK-renilla luciferase reporter to a luciferaselevel greater than 20% above background; and vb) inhibits the enzymaticactivity of recombinant 15-PGDH protein at an IC₅₀ of less than 1 μM.

In other embodiments, the 15-PGDH inhibitor can inhibit the enzymaticactivity of recombinant 15-PGDH at an IC₅₀ of less than 1 μM, orpreferably at an IC₅₀ of less than 250 nM, or more preferably at an IC₅₀of less than 50 nM, or more preferably at an IC₅₀ of less than 10 nM, ormore preferably at an IC₅₀ of less than 5 nM at a recombinant 15-PGDHconcentration of about 5 nM to about 10 nM.

In other embodiments, the 15-PGDH inhibitor can increase the cellularlevels of PGE-2 following stimulation of an A459 cell with anappropriate agent, for example IL1-beta.

In some embodiments, a 15-PGDH inhibitor can include a compound havingthe following formula (VIII):

-   -   wherein n is 0-2;    -   R¹, R⁶, and R⁷ are the same or different and are each selected        from the group consisting of hydrogen, substituted or        unsubstituted C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, C₂-C₂₄ alkynyl,        C₃-C₂₀ aryl, heteroaryl, heterocycloalkenyl containing from 5-6        ring atoms (wherein from 1-3 of the ring atoms is independently        selected from N, NH, N(C₁-C₆ alkyl), NC(O) (C₁-C₆ alkyl), O, and        S), C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, halo, —Si(C₁-C₃ alkyl)₃,        hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄        alkynyloxy, C₅-C₂₀ aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl        (—CO-alkyl) and C₆-C₂₀ arylcarbonyl (—CO-aryl)), acyloxy        (—O-acyl), C₂-C₂₄ alkoxycarbonyl (—(CO)—O-alkyl), C₆-C₂₀        aryloxycarbonyl (—(CO)—O-aryl), C₂-C₂₄ alkylcarbonato        (—O—(CO)—O-alkyl), C₆-C₂₀ arylcarbonato (—O—(CO)—O-aryl),        carboxy (—COOH), carboxylato (—COO⁻), carbamoyl (—(CO)—NH₂),        C₁-C₂₄ alkyl-carbamoyl (—(CO)—NH(C₁-C₂₄ alkyl)), arylcarbamoyl        (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH₂), carbamido        (—NH—(CO)—NH₂), cyano(—CN), isocyano (—N⁺C⁻), cyanato (—O—CN),        isocyanato (—O—N⁺═C⁻), isothiocyanato (—S—CN), azido (—N═N⁺═N⁻),        formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH₂), C₁-C₂₄        alkyl amino, C₅-C₂₀ aryl amino, C₂-C₂₄ alkylamido        (—NH—(CO)-alkyl), C₆-C₂₀ arylamido (—NH—(CO)-aryl), imino        (—CR═NH where R is hydrogen, C₁-C₂₄ alkyl, C₅-C₂₀ aryl, C₆-C₂₄        alkaryl, C₆-C₂₄ aralkyl, etc.), alkylimino (—CR═N(alkyl), where        R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino        (—CR═N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.),        nitro (—NO₂), nitroso (—NO), sulfo (—SO₂—OH), sulfonato        (—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl; also termed        “alkylthio”), arylsulfanyl (—S-aryl; also termed “arylthio”),        C₁-C₂₄ alkylsulfinyl (—(SO)-alkyl), C₅-C₂₀ arylsulfinyl        (—(SO)-aryl), C₁-C₂₄ alkylsulfonyl (—SO₂-alkyl), C₅-C₂₀        arylsulfonyl (—SO₂-aryl), sulfonamide (—SO₂—NH2, —SO₂NY₂        (wherein Y is independently H, aryl or alkyl), phosphono        (—P(O)(OH)₂), phosphonato (—P(O)(O⁻)₂), phosphinato (—P(O)(O⁻)),        phospho (—PO₂), phosphino (—PH₂), polyalkylethers, phosphates,        phosphate esters, groups incorporating amino acids or other        moieties expected to bear positive or negative charge at        physiological pH, combinations thereof, and wherein R⁶ and R⁷        may be linked to form a cyclic or polycyclic ring, wherein the        ring is a substituted or unsubstituted aryl, a substituted or        unsubstituted heteroaryl, a substituted or unsubstituted        cycloalkyl, and a substituted or unsubstituted heterocyclyl; and        pharmaceutically acceptable salts thereof.

15-PGDH inhibitors having formula (VIII) can be synthesized as shown:

Any reaction solvent can be used in the above preparation process aslong as it is not involved in the reaction. For example, the reactionsolvent includes ethers such as diethyl ether, tetrahydrofuran anddioxane; halogenized hydrocarbons, such as dichloromethane andchloroform; amines such as pyridine, piperidine and triethylamine;alkylketones, such as acetone, methylethylketone and methylisobutyl;alcohols, such as methanol, ethanol and propanol; non-protonic polarsolvent, such as N,N-dimethylformamide, N,N-dimethylacetamide,acetonitrile, dimethylsulfoxide and hexamethyl phosphoric acid triamide.Among non-reactive organic solvents that are ordinarily used in theorganic synthesis, preferable solvents are those from which watergenerated in the reaction can be removed by a Dean-Stark trap. Theexamples of such solvents include, but are not limited to benzene,toluene, xylene and the like. The reaction product thus obtained may beisolated and purified by condensation, extraction and the like, which isordinarily conducted in the field of the organic synthesis, if desired,by silica gel column chromatography. The individual enantiomers of PGDHinhibitors having the formula III can be separated by a preparative HPLCusing chromatography columns containing chiral stationary phases.

Further, embodiments of this application include any modifications forthe preparation method of the 15-PGDH inhibitors described above. Inthis connection, any intermediate product obtainable from any step ofthe preparation method can be used as a starting material in the othersteps. Such starting material can be formed in situ under certainreaction conditions. Reaction reagents can also be used in the form oftheir salts or optical isomers.

Depending on the kinds of the substituents to be used in the preparationof the 15-PGDH inhibitors, and the intermediate product and thepreparation method selected, novel 15-PGDH inhibitors can be in the formof any possible isomers such as substantially pure geometrical (cis ortrans) isomers, optical isomers (enantiomers) and racemates.

In some embodiments, a 15-PGDH inhibitor having formula (VIII) caninclude a compound with the following formula (IX):

-   -   and pharmaceutically acceptable salts thereof.

Advantageously, the 15-PDGH inhibitor having formula (IX) was found to:i) inhibit recombinant 15-PGDH at 1 nM concentration; ii) inhibit15-PGDH in cell lines at 100 nM concentration, iii) increase PGE₂production by cell lines; iv) is chemically stable in aqueous solutionsover broad pH range; v) is chemically stable when incubated withhepatocyte extracts, vi) is chemically stable when incubated withhepatocyte cell lines; vii) shows 253 minutes plasma half-life wheninjected IP into mice; and viii) shows no immediate toxicity over 24hours when injected IP into mice at 0.6 μmole/per mouse and at 1.2μmole/per mouse and also no toxicity when injected IP into mice at 0.3μmole/per mouse twice daily for 21 days.

In other embodiments, a 15-PGDH inhibitor having formula (IX) caninclude a compound with the following formula (IXa):

-   -   and pharmaceutically acceptable salts thereof.

In still other embodiments, a 15-PGDH inhibitor having formula (IX) caninclude a compound with the following formula (IXb):

-   -   and pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PDHG inhibitor can comprise a (+) or (−)optical isomer of a 15-PGDH inhibitor having formula (IX). In stillother embodiments, the 15-PDHG inhibitor can comprise a mixture at leastone of a (+) or (−) optical isomer of a 15-PGDH inhibitor having formula(IX). For example, the 15-PGDH inhibitor can comprise a mixture of: lessthan about 50% by weight of the (−) optical isomer of a 15-PGDHinhibitor having formula (IX) and greater than about 50% by weight ofthe (+) optical isomer of a 15-PGDH inhibitor having formula (IX), lessthan about 25% by weight of the (−) optical isomer of a 15-PGDHinhibitor having formula (IX) and greater than about 75% by weight ofthe (+) optical isomer of a 15-PGDH inhibitor having formula (IX), lessthan about 10% by weight of the (−) optical isomer of a 15-PGDHinhibitor having formula (IX) and greater than about 90% by weight ofthe (+) optical isomer of a 15-PGDH inhibitor having formula (IX), lessthan about 1% by weight of the (−) optical isomer of a 15-PGDH inhibitorhaving formula (IX) and greater than about 99% by weight of the (+)optical isomer of a 15-PGDH inhibitor having formula (IX), greater thanabout 50% by weight of the (−) optical isomer of a 15-PGDH inhibitorhaving formula (IX) and less than about 50% by weight of the (+) opticalisomer of a 15-PGDH inhibitor having formula (IX), greater than about75% by weight of the (−) optical isomer of a 15-PGDH inhibitor havingformula (IX) and less than about 25% by weight of the (+) optical isomerof a 15-PGDH inhibitor having formula (IX), greater than about 90% byweight of the (−) optical isomer of a 15-PGDH inhibitor having formula(IX) and less than about 10% by weight of the (+) optical isomer of a15-PGDH inhibitor having formula (IX), or greater than about 99% byweight of the (−) optical isomer of a 15-PGDH inhibitor having formula(IX) and less than about 1% by weight of the (+) optical isomer of a15-PGDH inhibitor having formula (IX).

In a still further embodiment, the 15-PDGH inhibitor can consistessentially of or consist of the (+) optical isomer of a 15-PGDHinhibitor having formula (IX). In yet another embodiment, the PDGHinhibitor can consist essentially of or consist of the (−) opticalisomer of a 15-PGDH inhibitor having formula (IX).

In other embodiments, a 15-PGDH inhibitor having formula (VIII) caninclude a compound with the following formula (X):

-   -   and pharmaceutically acceptable salts thereof.

Advantageously, the 15-PDGH inhibitor having formula (X) was found to:i) inhibit recombinant 15-PGDH at 3 nM concentration; ii) increase PGE₂production by cell lines at 20 nM; iii) is chemically stable in aqueoussolutions over broad pH range; iv) is chemically stable when incubatedwith mouse, rat and human liver extracts, v) shows 33 minutes plasmahalf-life when injected IP into mice; viii) shows no immediate toxicityover 24 hours when injected IP into mice at 50 mg/kg body weight, andix) is soluble in water (pH=3) at 1 mg/mL.

In other embodiments, a 15-PGDH inhibitor having formula (X) can includea compound with the following formula (Xa):

-   -   and pharmaceutically acceptable salts thereof.

In still other embodiments, a 15-PGDH inhibitor having formula (X) caninclude a compound with the following formula (Xb):

-   -   and pharmaceutically acceptable salts thereof.

In other embodiments, the 15-PDHG inhibitor can comprise a (+) or (−)optical isomer of a 15-PGDH inhibitor having formula (X). In still otherembodiments, the 15-PDHG inhibitor can comprise a mixture at least oneof a (+) or (−) optical isomer of a 15-PGDH inhibitor having formula(X). For example, the 15-PGDH inhibitor can comprise a mixture of: lessthan about 50% by weight of the (−) optical isomer of a 15-PGDHinhibitor having formula (X) and greater than about 50% by weight of the(+) optical isomer of a 15-PGDH inhibitor having formula (X), less thanabout 25% by weight of the (−) optical isomer of a 15-PGDH inhibitorhaving formula (X) and greater than about 75% by weight of the (+)optical isomer of a 15-PGDH inhibitor having formula (X), less thanabout 10% by weight of the (−) optical isomer of a 15-PGDH inhibitorhaving formula (X) and greater than about 90% by weight of the (+)optical isomer of a 15-PGDH inhibitor having formula (X), less thanabout 1% by weight of the (−) optical isomer of a 15-PGDH inhibitorhaving formula (X) and greater than about 99% by weight of the (+)optical isomer of a 15-PGDH inhibitor having formula (X), greater thanabout 50% by weight of the (−) optical isomer of a 15-PGDH inhibitorhaving formula (X) and less than about 50% by weight of the (+) opticalisomer of a 15-PGDH inhibitor having formula (X), greater than about 75%by weight of the (−) optical isomer of a 15-PGDH inhibitor havingformula (X) and less than about 25% by weight of the (+) optical isomerof a 15-PGDH inhibitor having formula (X), greater than about 90% byweight of the (−) optical isomer of a 15-PGDH inhibitor having formula(X) and less than about 10% by weight of the (+) optical isomer of a15-PGDH inhibitor having formula (X), or greater than about 99% byweight of the (−) optical isomer of a 15-PGDH inhibitor having formula(X) and less than about 1% by weight of the (+) optical isomer of a15-PGDH inhibitor having formula (X).

In a still further embodiment, the 15-PDGH inhibitor can consistessentially of or consist of the (+) optical isomer of a 15-PGDHinhibitor having formula (X). In yet another embodiment, the PDGHinhibitor can consist essentially of or consist of the (−) opticalisomer of a 15-PGDH inhibitor having formula (X).

It will be appreciated that the other 15-PGDH inhibitors can be used inthe methods described herein. These other 15-PGDH inhibitors can includeknown 15-PGDH inhibitors including, for example, tetrazole compounds offormulas (I) and (II), 2-alkylideneaminooxyacetamidecompounds of formula(I), heterocyclic compounds of formulas (VI) and (VII), and pyrazolecompounds of formula (III) described in U.S. Patent ApplicationPublication No. 2006/0034786 and U.S. Pat. No. 7,705,041;benzylidene-1,3-thiazolidine compounds of formula (I) described in U.S.Patent Application Publication No. 2007/0071699;phenylfurylmethylthiazolidine-2,4-dione andphenylthienylmethylthiazolidine-2,4-dione compounds described in U.S.Patent Application Publication No. 2007/0078175; thiazolidenedionederivatives described in U.S. Patent Application Publication No.2011/0269954; phenylfuran, phenylthiophene, or phenylpyrrazole compoundsdescribed in U.S. Pat. No. 7,294,641, 5-(3,5-disubstitutedphenylazo)-2-hydroxybenzene-acetic acids and salts and lactonesdescribed in U.S. Pat. No. 4,725,676, and azo compounds described inU.S. Pat. No. 4,889,846.

Still other examples are described in the following publications: Seo SY et al. Effect of 15-hydroxyprostaglandin dehydrogenase inhibitor onwound healing. Prostaglandins Leukot Essent Fatty Acids. 2015; 97:35-41.doi: 10.1016/j.plefa.2015.03.005. PubMed PMID: 25899574; Piao Y L et al.Wound healing effects of new 15-hydroxyprostaglandin dehydrogenaseinhibitors. Prostaglandins Leukot Essent Fatty Acids. 2014;91(6):325-32. doi: 10.1016/j.plefa.2014.09.011. PubMed PMID: 25458900;Choi D et al. Control of the intracellular levels of prostaglandin E(2)through inhibition of the 15-hydroxyprostaglandin dehydrogenase forwound healing. Bioorg Med Chem. 2013; 21(15):4477-84. doi:10.1016/j.bmc.2013.05.049. PubMed PMID: 23791868; Wu Y et al. Synthesisand biological evaluation of novel thiazolidinedione analogues as15-hydroxyprostaglandin dehydrogenase inhibitors. J Med Chem. 2011;54(14):5260-4. Epub 2011/06/10. doi: 10.1021/jm200390u. PubMed PMID:21650226; Duveau D Y et al. Structure-activity relationship studies andbiological characterization of human NAD(+)-dependent15-hydroxyprostaglandin dehydrogenase inhibitors. Bioorg Med Chem Lett.2014; 24(2):630-5. doi: 10.1016/j.bmcl.2013.11.081. PubMed PMID:24360556; PMCID: PMC3970110; Duveau D Y et al. Discovery of two smallmolecule inhibitors, ML387 and ML388, of human NAD+-dependent15-hydroxyprostaglandin dehydrogenase. Probe Reports from the NIHMolecular Libraries Program. Bethesda (Md.)2010; Wu Y et al. Synthesisand SAR of thiazolidinedione derivatives as 15-PGDH inhibitors. BioorgMed Chem. 2010; 18(4):1428-33. doi: 10.1016/j.bmc.2010.01.016. PubMedPMID: 20122835; Wu Y et al. Synthesis and biological evaluation of novelthiazolidinedione analogues as 15-hydroxyprostaglandin dehydrogenaseinhibitors. J Med Chem. 2011; 54(14):5260-4. Epub 2011/06/10. doi:10.1021/jm200390u. PubMed PMID: 21650226; Jadhav A et al. Potent andselective inhibitors of NAD+-dependent 15-hydroxyprostaglandindehydrogenase (HPGD). Probe Reports from the NIH Molecular LibrariesProgram. Bethesda (Md.)2010; Niesen F H et al. High-affinity inhibitorsof human NAD-dependent 15-hydroxyprostaglandin dehydrogenase: mechanismsof inhibition and structure-activity relationships. PLoS One. 2010;5(11):e13719. Epub 2010/11/13. doi: 10.1371/journal.pone.0013719. PubMedPMID: 21072165; PMCID: 2970562; Michelet, J. et al. Compositioncomprising at least one 15-PGDH inhibitor. US20080206320 A1, 2008; andRozot, R et al. Care/makeup compositions comprising a2-alkylideneaminooxyacetamide compound for stimulating the growth of thehair or eyelashes and/or slowing loss thereof. U.S. Pat. No. 7,396,525B2, 2008.

The 15-PGDH inhibitors described herein can be provided in apharmaceutical composition. A pharmaceutical composition containing the15-PGDH inhibitors described herein as an active ingredient may bemanufactured by mixing the derivative with a pharmaceutically acceptablecarrier(s) or an excipient(s) or diluting the 15-PGDH inhibitors with adiluent in accordance with conventional methods. The pharmaceuticalcomposition may further contain fillers, anti-cohesives, lubricants,wetting agents, flavoring agents, emulsifying agents, preservatives andthe like. The pharmaceutical composition may be formulated into asuitable formulation in accordance with the methods known to thoseskilled in the art so that it can provide an immediate, controlled orsustained release of the 15-PGDH inhibitors after being administeredinto a mammal.

In some embodiments, the pharmaceutical composition may be formulatedinto a parenteral or oral dosage form. The solid dosage form for oraladministration may be manufactured by adding excipient, if necessary,together with binder, disintegrants, lubricants, coloring agents, and/orflavoring agents, to the 15-PGDH inhibitors and shaping the resultingmixture into the form of tablets, sugar-coated pills, granules, powderor capsules. The additives that can be added in the composition may beordinary ones in the art. For example, examples of the excipient includelactose, sucrose, sodium chloride, glucose, starch, calcium carbonate,kaolin, microcrystalline cellulose, silicate and the like. Exemplarybinders include water, ethanol, propanol, sweet syrup, sucrose solution,starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose,shellac, calcium phosphonate and polypyrrolidone. Examples of thedisintegrant include dry starch, sodium arginate, agar powder, sodiumbicarbonate, calcium carbonate, sodium lauryl sulfate, stearicmonoglyceride and lactose. Further, purified talc, stearates, sodiumborate, and polyethylene glycol may be used as a lubricant; and sucrose,bitter orange peel, citric acid, tartaric acid, may be used as aflavoring agent. In some embodiments, the pharmaceutical composition canbe made into aerosol formulations (e.g., they can be nebulized) to beadministered via inhalation.

The 15-PGDH inhibitors described herein may be combined with flavoringagents, buffers, stabilizing agents, and the like and incorporated intooral liquid dosage forms such as solutions, syrups or elixirs inaccordance with conventional methods. One example of the buffers may besodium citrate. Examples of the stabilizing agents include tragacanth,acacia and gelatin.

In some embodiments, the 15-PGDH inhibitors described herein may beincorporated into an injection dosage form, for example, for asubcutaneous, intramuscular or intravenous route by adding thereto pHadjusters, buffers, stabilizing agents, relaxants, topical anesthetics.Examples of the pH adjusters and the buffers include sodium citrate,sodium acetate and sodium phosphate. Examples of the stabilizing agentsinclude sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid.The topical anesthetics may be procaine HCl, lidocaine HCl and the like.The relaxants may be sodium chloride, glucose and the like.

In other embodiments, the 15-PGDH inhibitors described herein may beincorporated into suppositories in accordance with conventional methodsby adding thereto pharmaceutically acceptable carriers that are known inthe art, for example, polyethylene glycol, lanolin, cacao butter orfatty acid triglycerides, if necessary, together with surfactants suchas Tween.

The pharmaceutical composition may be formulated into various dosageforms as discussed above and then administered through various routesincluding an oral, inhalational, transdermal, subcutaneous, intravenousor intramuscular route. The dosage can be a pharmaceutically ortherapeutically effective amount.

Therapeutically effective dosage amounts of the 15-PGDH inhibitor may bepresent in varying amounts in various embodiments. For example, in someembodiments, a therapeutically effective amount of the 15-PGDH inhibitormay be an amount ranging from about 10-1000 mg (e.g., about 20 mg-1,000mg, 30 mg-1,000 mg, 40 mg-1,000 mg, 50 mg-1,000 mg, 60 mg-1,000 mg, 70mg-1,000 mg, 80 mg-1,000 mg, 90 mg-1,000 mg, about 10-900 mg, 10-800 mg,10-700 mg, 10-600 mg, 10-500 mg, 100-1000 mg, 100-900 mg, 100-800 mg,100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 200-1000 mg,200-900 mg, 200-800 mg, 200-700 mg, 200-600 mg, 200-500 mg, 200-400 mg,300-1000 mg, 300-900 mg, 300-800 mg, 300-700 mg, 300-600 mg, 300-500 mg,400 mg-1,000 mg, 500 mg-1,000 mg, 100 mg-900 mg, 200 mg-800 mg, 300mg-700 mg, 400 mg-700 mg, and 500 mg-600 mg). In some embodiments, the15-PGDH inhibitor is present in an amount of or greater than about 10mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg. In someembodiments, the 15-PGDH inhibitor is present in an amount of or lessthan about 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650mg, 600 mg, 550 mg, 500 mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200mg, 150 mg, or 100 mg.

In other embodiments, a therapeutically effective dosage amount may be,for example, about 0.001 mg/kg weight to 500 mg/kg weight, e.g., fromabout 0.001 mg/kg weight to 400 mg/kg weight, from about 0.001 mg/kgweight to 300 mg/kg weight, from about 0.001 mg/kg weight to 200 mg/kgweight, from about 0.001 mg/kg weight to 100 mg/kg weight, from about0.001 mg/kg weight to 90 mg/kg weight, from about 0.001 mg/kg weight to80 mg/kg weight, from about 0.001 mg/kg weight to 70 mg/kg weight, fromabout 0.001 mg/kg weight to 60 mg/kg weight, from about 0.001 mg/kgweight to 50 mg/kg weight, from about 0.001 mg/kg weight to 40 mg/kgweight, from about 0.001 mg/kg weight to 30 mg/kg weight, from about0.001 mg/kg weight to 25 mg/kg weight, from about 0.001 mg/kg weight to20 mg/kg weight, from about 0.001 mg/kg weight to 15 mg/kg weight, fromabout 0.001 mg/kg weight to 10 mg/kg weight.

In still other embodiments, a therapeutically effective dosage amountmay be, for example, about 0.0001 mg/kg weight to 0.1 mg/kg weight, e.g.from about 0.0001 mg/kg weight to 0.09 mg/kg weight, from about 0.0001mg/kg weight to 0.08 mg/kg weight, from about 0.0001 mg/kg weight to0.07 mg/kg weight, from about 0.0001 mg/kg weight to 0.06 mg/kg weight,from about 0.0001 mg/kg weight to 0.05 mg/kg weight, from about 0.0001mg/kg weight to about 0.04 mg/kg weight, from about 0.0001 mg/kg weightto 0.03 mg/kg weight, from about 0.0001 mg/kg weight to 0.02 mg/kgweight, from about 0.0001 mg/kg weight to 0.019 mg/kg weight, from about0.0001 mg/kg weight to 0.018 mg/kg weight, from about 0.0001 mg/kgweight to 0.017 mg/kg weight, from about 0.0001 mg/kg weight to 0.016mg/kg weight, from about 0.0001 mg/kg weight to 0.015 mg/kg weight, fromabout 0.0001 mg/kg weight to 0.014 mg/kg weight, from about 0.0001 mg/kgweight to 0.013 mg/kg weight, from about 0.0001 mg/kg weight to 0.012mg/kg weight, from about 0.0001 mg/kg weight to 0.011 mg/kg weight, fromabout 0.0001 mg/kg weight to 0.01 mg/kg weight, from about 0.0001 mg/kgweight to 0.009 mg/kg weight, from about 0.0001 mg/kg weight to 0.008mg/kg weight, from about 0.0001 mg/kg weight to 0.007 mg/kg weight, fromabout 0.0001 mg/kg weight to 0.006 mg/kg weight, from about 0.0001 mg/kgweight to 0.005 mg/kg weight, from about 0.0001 mg/kg weight to 0.004mg/kg weight, from about 0.0001 mg/kg weight to 0.003 mg/kg weight, fromabout 0.0001 mg/kg weight to 0.002 mg/kg weight. In some embodiments,the therapeutically effective dose may be 0.0001 mg/kg weight, 0.0002mg/kg weight, 0.0003 mg/kg weight, 0.0004 mg/kg weight, 0.0005 mg/kgweight, 0.0006 mg/kg weight, 0.0007 mg/kg weight, 0.0008 mg/kg weight,0.0009 mg/kg weight, 0.001 mg/kg weight, 0.002 mg/kg weight, 0.003 mg/kgweight, 0.004 mg/kg weight, 0.005 mg/kg weight, 0.006 mg/kg weight,0.007 mg/kg weight, 0.008 mg/kg weight, 0.009 mg/kg weight, 0.01 mg/kgweight, 0.02 mg/kg weight, 0.03 mg/kg weight, 0.04 mg/kg weight, 0.05mg/kg weight, 0.06 mg/kg weight, 0.07 mg/kg weight, 0.08 mg/kg weight,0.09 mg/kg weight, or 0.1 mg/kg weight. The effective dose for aparticular individual can be varied (e.g., increased or decreased) overtime, depending on the needs of the individual.

In some embodiments, a therapeutically effective dosage may be a dosageof 10 μg/kg/day, 50 μg/kg/day, 100 μg/kg/day, 250 μg/kg/day, 500μg/kg/day, 1000 μg/kg/day or more. In various embodiments, the amount ofthe 15-PGDH inhibitor or pharmaceutical salt thereof is sufficient toprovide a dosage to a patient of between 0.01 μg/kg and 10 μg/kg; 0.1μg/kg and 5 μg/kg; 0.1 μg/kg and 1000 μg/kg; 0.1 μg/kg and 900 μg/kg;0.1 μg/kg and 900 μg/kg; 0.1 μg/kg and 800 μg/kg; 0.1 μg/kg and 700μg/kg; 0.1 μg/kg and 600 μg/kg; 0.1 μg/kg and 500 μg/kg; or 0.1 μg/kgand 400 μg/kg.

Particular doses or amounts to be administered in accordance with thepresent invention may vary, for example, depending on the nature and/orextent of the desired outcome, on particulars of route and/or timing ofadministration, and/or on one or more characteristics (e.g., weight,age, personal history, genetic characteristic, lifestyle parameter,severity of cardiac defect and/or level of risk of cardiac defect, etc.,or combinations thereof). Such doses or amounts can be determined bythose of ordinary skill. In some embodiments, an appropriate dose oramount is determined in accordance with standard clinical techniques.For example, in some embodiments, an appropriate dose or amount is adose or amount sufficient to reduce a disease severity index score by 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or more.For example, in some embodiments, an appropriate dose or amount is adose or amount sufficient to reduce a disease severity index score by 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100%.Alternatively or additionally, in some embodiments, an appropriate doseor amount is determined through use of one or more in vitro or in vivoassays to help identify desirable or optimal dosage ranges or amounts tobe administered.

Various embodiments may include differing dosing regimen. In someembodiments, the 15-PGDH inhibitor can be administered via continuousinfusion. In some embodiments, the continuous infusion is intravenous.In other embodiments, the continuous infusion is subcutaneous.Alternatively or additionally, in some embodiments, the 15-PGDHinhibitor can be administered bimonthly, monthly, twice monthly,triweekly, biweekly, weekly, twice weekly, thrice weekly, daily, twicedaily, or on another clinically desirable dosing schedule. The dosingregimen for a single subject need not be at a fixed interval, but can bevaried over time, depending on the needs of the subject.

For topical application, the composition can be administered in the formof aqueous, alcoholic, aqueous-alcoholic or oily solutions orsuspensions, or of a dispersion of the lotion or serum type, ofemulsions that have a liquid or semi-liquid consistency or are pasty,obtained by dispersion of a fatty phase in an aqueous phase (O/W) orvice versa (W/O) or multiple emulsions, of a free or compacted powder tobe used as it is or to be incorporated into a physiologically acceptablemedium, or else of microcapsules or microparticles, or of vesiculardispersions of ionic and/or nonionic type. It may thus be in the form ofa salve, a tincture, milks, a cream, an ointment, a powder, a patch, animpregnated pad, a solution, an emulsion or a vesicular dispersion, alotion, aqueous or anhydrous gels, a spray, a suspension, a shampoo, anaerosol or a foam. It may be anhydrous or aqueous. It may also comprisesolid preparations constituting soaps or cleansing cakes.

Pharmaceutical compositions including the 15-PGDH inhibitor describedherein can additionally contain, for example, at least one compoundchosen from prostaglandins, in particular prostaglandin PGE₁, PGE₂,their salts, their esters, their analogues and their derivatives, inparticular those described in WO 98/33497, WO 95/11003, JP 97-100091, JP96-134242, in particular agonists of the prostaglandin receptors. It mayin particular contain at least one compound such as the agonists (inacid form or in the form of a precursor, in particular in ester form) ofthe prostaglandin F₂u receptor, such as for example latanoprost,fluprostenol, cloprostenol, bimatoprost, unoprostone, the agonists (andtheir precursors, in particular the esters such as travoprost) of theprostaglandin E₂ receptors such as 17-phenyl PGE₂, viprostol, butaprost,misoprostol, sulprostone, 16,16-dimethyl PGE₂, 11-deoxy PGE₁, 1-deoxyPGE₁, the agonists and their precursors, in particular esters, of theprostacycline (IP) receptor such as cicaprost, iloprost,isocarbacycline, beraprost, eprostenol, treprostinil, the agonists andtheir precursors, in particular the esters, of the prostaglandin D₂receptor such as BW245C((4S)-(3-[(3R,S)-3-cyclohexyl-3-isopropyl]-2,5-dioxo)-4-imidazolidinehept-anoicacid), BW246C((4R)-(3-[(3R,S)-3-cyclohexyl-3-isopropyl]-2,5-dioxo)-4-imidazolidinehept-anoicacid), the agonists and their precursors, in particular the esters, ofthe receptor for the thromboxanes A2 (TP) such as I-BOP ([1S-[1a,2a(Z),3b(1E,3S),4a]]-7-[3-[3-hydroxy-4-[4-(iodophenoxy)-1-butenyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoicacid).

Advantageously, the composition can include at least one 15-PGDHinhibitor as defined above and at least one prostaglandin or oneprostaglandin derivative such as for example the prostaglandins ofseries 2 including in particular PGF_(2α) and PGE₂ in saline form or inthe form of precursors, in particular of the esters (example isopropylesters), their derivatives such as 16,16-dimethyl PGE₂, 17-phenyl PGE₂and 16,16-dimethyl PGF_(2α) 17-phenyl PGF_(2α), prostaglandins of series1 such as 11-deoxyprostaglandin E1, 1-deoxyprostaglandin E1 in saline orester form, is their analogues, in particular latanoprost, travoprost,fluprostenol, unoprostone, bimatoprost, cloprostenol, viprostol,butaprost, misoprostol, their salts or their esters.

In other embodiments, the 15-PGDH inhibitor can be administered with oneor more additional chemotherapeutic or cardioprotective agents ortreatments or in combination with one or more chemotherapeutic regimensknown in the field of oncology. “In combination” or “in combinationwith,” as used herein, means in the course of treating the same diseasein the same patient using two or more agents, drugs, treatment regimens,treatment modalities or a combination thereof, in any order. Thisincludes simultaneous administration, as well as in a temporally spacedorder of up to several days apart. Such combination treatment may alsoinclude more than a single administration of any one or more of theagents, drugs, treatment regimens or treatment modalities. Further, theadministration of the two or more agents, drugs, treatment regimens,treatment modalities or a combination thereof may be by the same ordifferent routes of administration.

Examples of cardioprotective agents or treatments that may be used inaccordance with the methods described herein include, but are notlimited to, cardioprotective drugs (e.g., dexrazoxane, ACE-inhibitors,diuretics, cardiac glycosides) cholesterol lowering drugs,revascularization drugs, anti-inflammatory drugs, cardioprotectivediets, cardioprotective nutrients, cardioprotective herbs,cardioprotective vitamins (e.g., folic acid, B vitamin family), andcardioprotective hormone treatments.

In some embodiments, the 15-PGDH inhibitor can be administered incombination with a therapeutically amount of SDF-1. The SDF-1 can beadministered by injecting a solution comprising SDF-1 expressing plasmidin the heart of a subject in need of treatment. The SDF-1 can beexpressed from the heart at an amount effective to improve leftventrical ejection fraction.

In an aspect of the application, the SDF-1 plasmid can be administeredto the heart in multiple injections of the solution with each injectioncomprising about 0.33 mg/ml to about 5 mg/ml of SDF-1 plasmid solution.In one example, the SDF-1 plasmid can be administered to a weakened,ischemic, and/or peri-infarct region of the heart in at least about 10injections. Each injection administered to the heart can have a volumeof at least about 0.2 ml. The SDF-1 can be expressed in the heart forgreater than about three days.

The invention is further illustrated by the following example, which isnot intended to limit the scope of the claims.

Example

This example shows results from a study in which (+) SW033291, a 15-PGDHinhibitor, prevented doxorubicin induced cardiomyopathy in mice.Doxorubicin induced cardiomyopathy limits the total doxorubicin dosethat can be administered to cancer patients. Preventing this effectwould directly reduce risk of cardiomyopathy arising in cancer patientsreceiving doxorubicin containing regimes, and would also mean thatcancer patients would not have to discontinue receiving effectivedoxorubicin based therapies when the total doxorubicin dose reaches thecurrent cardiotoxicity based dose limit.

FIG. 1 illustrates schematically the design of a study in which maleC57bl6J mice received 15 mpk cumulative dose of doxorubicin in 7 dosesof 2.15 mpk administered daily over study days 1-7. A 15-PGDH inhibitor,(+) SW033291, was administered by oral gavage at a dose of 25 mpk twicedaily over study days 1-14, as a solution in a vehicle of 10% ethanoland 90% soybean oil. Cardiac ejection fraction was determined byechocardiography on study days 14 and 28.

FIG. 2 illustrates a graph showing cardiac ejection fraction at studyday 1, at the start of the experiment, at study day 14 and at study day28. Black bars show measurement in control mice receiving either oralsaline or oral vehicle. Blue bars show results in doxorubicin treatedmice receiving oral vehicle. Red bars show results in doxorubicintreated mice also receiving (+) SW033291. Doxorubicin treated micereceiving oral vehicle (blue bars) show a 10% decrease in ejectionfraction on day 14 and day 28 as compared to non-doxorubicin treatedcontrol mice receiving vehicle only for 14 days. In contrast, micetreated with both doxorubicin and (+) SW033291 only a 2% (day 14) or1.5% (day 28) decrease in ejection fraction. The difference in ejectionfraction in doxorubicin treated mice receiving or not receiving (+)SW033291 was statiscally significant (P<0.05) on both days 14 and 28.

FIG. 3 illustrates representative echocardiograms on study day 14 ofdoxorubicin treated mice receiving either oral vehicle (upper panel) ororal (+) SW033291 (lower panel), showing the markedly greater cardiaccontractility in the (+) SW033291 treated mouse.

FIG. 4 illustrates induction of DNA damage in cardiac myocytes ofdoxorubicin treated mice as visualized by immunostaining for gamma-H2AX.

FIG. 5 illustrates images and graphs showing that doxorubicin inducesequal levels of DNA damage in mice receiving oral (+) SW033291 as inmice receiving oral vehicle, as assayed by gamma-H2AX immunostaining.

FIG. 6 shows the design of a second follow on study (Set B) in whichmice were treated with 2 consecutive cycles of doxorubicin.

FIG. 7 shows results for the ejection fraction (EF %) of the firstcohort of mice (Set A) graphed in FIG. 2 , but with follow-up nowextended to day 56, showing maintenance of improvement in ejectionfraction in mice that had received treatment with (+)-SW033291. FIG. 7also shows the improvement of ejection fraction in (+)-SW033291 treatedmice from Set B demonstrated both at day 14, following one the firstcycle of treatment with doxorubicin, and at day 42 following the secondcycle of treatment with doxorubicin.

FIG. 8 shows further analysis of mice from Set B, showing that on day42, after two cycles of doxorubicin, (+)-SW033291 treated mice havegreater total body weight than vehicle treated mice, (+)-SW033291treated mice have lesser ventricular weight than vehicle control treatedmice, and (+)-SW033291 treated mice have lesser lung weight than vehiclecontrol treated mice, all of which metrics accord with the improvedcardiac function of the (+)-SW033291 treated mice.

FIG. 9 shows further analysis of mice from Set B, showing that on day42, after two cycles of doxorubicin, (+)-SW033291 treated mice havelower levels of atrial natriuretic factor (as measured by real-time PCRin cardiac tissue) than do vehicle control treated mice, consistent withthe improved cardiac function of these mice.

FIG. 10 shows further analysis of mice from Set B, showing that on day42, after two cycles of doxorubicin, (+)-SW033291 treated mice havelower levels of expression of connective tissue growth factor (asmeasured by real-time PCR in cardiac tissue) than do vehicle controltreated mice, consistent with development of lesser cardiac fibrosis inthe (+)-SW033291 treated mice.

FIG. 11 shows that administering 25 mpk of oral (+)-SW033291 inhibitsactivity of cardiac 15-PGDH by approximately 80% starting at 30 minutesafter drug treatment and persisting for 3 hours following drugadministration. Mice treated with (+)-SW033291 also showed increasedcardiac PGE2 at 6 hours after drug treatment, presumably reflecting thetime required for PGE2 to accumulate in the tissue following inhibitionof 15-PGDH.

These results demonstrate that the 15-PGDH inhibitor (+) SW033291protects from doxorubicin induced cardiomyopathy by modifying theeffects of cardiac injury. Moreover, the data indicate that 15-PGDHinhibition does not compromise the chemotherapeutic efficacy ofdoxorubicin.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims. All patents, publications andreferences cited in the foregoing specification are herein incorporatedby reference in their entirety.

1-26. (canceled) 27: A method of treating cardiotoxicity in a subject inneed thereof, the method comprising: administering to the subject atherapeutically effective amount of a 15-PGDH inhibitor. 28: The methodof claim 27, wherein the cardiotoxicity includes a reduction of cardiacejection fraction of at least about 10% and the 15-PGDH inhibitor isadministered to the subject at an amount effective to increase cardiacejection fraction by at least 10%. 29: The method of claim 28, whereinthe subject has or is at risk of hypertension. 30: The method of claim27, wherein the cardiotoxicity is induced by treatment of the subjectwith a cardiotoxic agent. 31: The method of claim 30, wherein thecardiotoxic agent is a chemotherapeutic. 32: The method of claim 30,wherein the cardiotoxic agent is selected from doxorubicin, epirubicin,daunorubicin, idarubicin, valrubicin, pirarubicin, amrubicin,aclarubicin, zorubicin, an anti-ErB2 or an anti-HER2 antibody. 33: Amethod of treating a cardiomyopathy and/or a reduction of cardiacejection fraction resulting from hypertension or cardiotoxicity in asubject in need thereof, the method comprising: administering to thesubject a therapeutically effective amount of a 15-PGDH inhibitor. 34:The method of claim 33, wherein the cardiomyopathy and/or reduction ofcardiac ejection fraction is induced by treatment of the subject with acardiotoxic agent. 35: The method of claim 34, wherein the cardiotoxicagent is a chemotherapeutic. 36: The method of claim 35, wherein thecardiotoxic agent is selected from doxorubicin, epirubicin,daunorubicin, idarubicin, valrubicin, pirarubicin, amrubicin,aclarubicin, zorubicin, an anti-ErB2 or an anti-HER2 antibody. 37: Themethod of claim 33, wherein the subject has or is at risk ofhypertension.